Journal Articles

Enfortumab vedotin induces immunogenic cell death and shows enhanced preclinical antitumor activity when combined with a PD-1 inhibitor Featured  

(1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

Cell reports. Medicine

Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

(1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

Cell reports. Medicine

Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

ABSTRACT: Enfortumab vedotin is a Nectin-4-directed antibody-drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4-positive tumor cells, indirect bystander effect on neighboring Nectin-4-negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells results in protection against tumor rechallenge in mice, consistent with antitumor immunity. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical findings provide mechanistic hypotheses that may be relevant to the improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy.

Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer,

Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer, Inc., Bothell, WA 98021, USA. (6) Pfizer, Inc., Bothell, WA 98021, USA. (7) Pfizer, Inc., Bothell, WA 98021, USA. (8) Seagen, Inc., Bothell, WA 98021, USA. (9) Pfizer, Inc., Bothell, WA 98021, USA. (10) Pfizer, Inc., Bothell, WA 98021, USA. (11) Pfizer, Inc., Bothell, WA 98021, USA. (12) Seagen, Inc., Bothell, WA 98021, USA. (13) Seagen, Inc., Bothell, WA 98021, USA. (14) Pfizer, Inc., Bothell, WA 98021, USA. (15) Pfizer, Inc., Bothell, WA 98021, USA. (16) Seagen, Inc., Bothell, WA 98021, USA. (17) Seagen, Inc., Bothell, WA 98021, USA. (18) Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. (19) Astellas Research Institute of America LLC, Northbrook, IL 60062, USA. (20) Pfizer, Inc., Bothell, WA 98021, USA. (21) Pfizer, Inc., Bothell, WA 98021, USA. (22) Pfizer, Inc., Bothell, WA 98021, USA. Electronic address: sharsti.sandall@pfizer.com.

Citation: Cell Rep Med 2026 Sep 2 103021 Epub09/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42685702

Tags:

Tumor immune microenvironment remodeling predicts response to checkpoint inhibitor therapy Spotlight 

(1) Lin Z (2) Chandra M (3) Srinivas N (4) Ugurel S (5) Becker JC (6) Aran D

Cancer cell

Lin et al. developed a longitudinal scRNAseq atlas of 441 ICI-treated tumors from 241 patients across 10 cancer types, and identified 4 conserved TIME states. ICI induced temporal TIME remodeling with early T cell activation, resolution of distinct ISG patterns, and progressive stromal and immune restructuring. During treatment, approximately 40% of tumors transitioned between TIME states, with inflamed or B cell-enriched transitions associated with response and survival, while myeloid-dominant states associated with resistance. A baseline 59-gene transition signature was predictive of ICI response and survival across 1,383 tumors from 19 independent cohorts.

Contributed by Shishir Pant

(1) Lin Z (2) Chandra M (3) Srinivas N (4) Ugurel S (5) Becker JC (6) Aran D

Cancer cell

Lin et al. developed a longitudinal scRNAseq atlas of 441 ICI-treated tumors from 241 patients across 10 cancer types, and identified 4 conserved TIME states. ICI induced temporal TIME remodeling with early T cell activation, resolution of distinct ISG patterns, and progressive stromal and immune restructuring. During treatment, approximately 40% of tumors transitioned between TIME states, with inflamed or B cell-enriched transitions associated with response and survival, while myeloid-dominant states associated with resistance. A baseline 59-gene transition signature was predictive of ICI response and survival across 1,383 tumors from 19 independent cohorts.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet the basis of variable patient responses remains unclear. We assemble a longitudinal single-cell RNA sequencing atlas of 441 samples from 241 patients across ten cancer entities to map treatment-associated remodeling of the tumor immune microenvironment (TIME). With a hierarchical reference-guided deep-phenotyping framework, we define 77 immune and stromal subtypes and resolve four conserved TIME subtypes. Approximately 40% of tumors shift between states during therapy, and the transition is more predictive of outcome than the baseline state. Favorable transitions toward inflamed or B cell-enriched subtype track with improved response and survival, while persistence in or shifts toward myeloid dominance indicate resistance. We derive a 59-gene signature that predicted response and survival for 1,383 baseline tumors across 19 independent cohorts. These findings establish immunotype transitions as a central determinant of ICI efficacy, offering new avenues for response prediction and rational immunotherapy design.

Author Info: (1) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (2) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical

Author Info: (1) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (2) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. (4) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. (5) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address: j.becker@dkfz-heidelberg.de. (6) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel; The Taub Faculty of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: dviraran@technion.ac.il.

Citation: Cancer Cell 2026 Sep 1 Epub09/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42679812

Tags:

Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization Spotlight 

(1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J

Science

Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.

Contributed by Shishir Pant

(1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J

Science

Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.

Contributed by Shishir Pant

ABSTRACT: The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdh(high) DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1(high) interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

Author Info: (1) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Insti

Author Info: (1) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (2) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. (3) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (4) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (5) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (6) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (7) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (8) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (9) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (10) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (11) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (12) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (13) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (14) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (15) BGI Research, Chongqing, China. Department of Neurology, Hubei Provincial Clinical Research Center for Parkinson's Disease, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China. (16) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (17) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (18) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (19) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (20) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (21) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (22) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (23) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. First Hospital of Shanxi Medical University, Taiyuan, China. Molecular Imaging Precision Medical Collaborative Innovation Center, Shanxi Medical University, Taiyuan, China. (24) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (25) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (26) Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. (27) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (28) BGI Research, Hangzhou, China. (29) BGI Research, Chongqing, China. (30) BGI Research, Chongqing, China. (31) BGI Research, Chongqing, China. (32) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (33) BGI Research, Hangzhou, China. (34) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. BGI, Shenzhen, China. (35) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Stomatology, Zhongshan Hospital Fudan University, Shanghai, China. (36) 3DC STAR Lab, BGI CELL, Shenzhen, China. Prince Fahad bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia. (37) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (38) BGI Research, Chongqing, China. JFL-BGI STOmics Center, Jinfeng Laboratory, Chongqing, China. (39) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (40) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (41) Dunwill Med-Tech, Shanghai, China. (42) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (43) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (44) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (45) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.

Citation: Science 2026 Jul 30 393:eadz7928 Epub07/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42531396

Tags:

UV irradiation drives lineage-specific MITF-mediated transcription of PD-L1 to confer immune tolerance to UV-mutated melanocytes Featured  

(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE

Immunity

Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.

(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE

Immunity

Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.

ABSTRACT: UV radiation (UVR) drives high mutational burdens, yet precursor melanocytes accumulate these mutations without triggering immune clearance. Here, we investigated whether melanocyte-intrinsic transcriptional program(s) underlie immune tolerance to mutations resulting from UVR exposure. In primary human melanocytes, expression of PD-L1 (CD274) was dependent on microphthalmia-associated transcription factor (MITF), a crucial regulator of melanocyte development and an intermediate in the UV-tanning pathway. MITF directly activated PD-L1 transcription by binding a conserved upstream enhancer containing functional E-box elements. MITF determined both baseline melanocytic PD-L1 expression in healthy skin and its induction following UVR, independent of interferon signaling. Melanocyte-restricted Pd-l1 deletion in mice triggered CD8(+) T cell infiltration and depigmentation after long-term UVB exposure, recapitulating features of human vitiligo. PD-L1-deficient human induced pluripotent stem cell (iPSC)-derived melanocytes underwent increased apoptosis and were more susceptible than PD-L1-intact melanocytes to gp100-specific CD8(+) T cell killing. Thus, a melanocyte-intrinsic MITF-PD-L1 tolerance program protects melanocytes from autoimmune destruction, potentially facilitating early immune evasion during melanoma development and conversely underlying the responsiveness of melanoma to PD-1/PD-L1 blockade.

Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth

Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (3) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (4) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (5) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan. (6) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (7) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (8) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (9) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (10) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Stomatology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. (11) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (12) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest 1085, Hungary; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest 1085, Hungary; MTA-SE LendŸlet "Momentum" Dermatology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Hungary. (13) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (14) Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Dermatology Service, San Francisco Veterans Administration Health Care System, San Francisco, CA 94121, USA. (15) Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel; Center for Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Jerusalem 91120, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel. (16) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (17) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (18) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland. (19) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA. (20) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) IStem, CECS, Corbeil-Essonnes 91100, France. (23) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (24) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (25) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (26) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02142, USA. (29) Mass General Brigham Cancer Institute, Boston, MA 02114, USA. (30) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (32) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (34) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA. (35) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. Electronic address: jeallouche@gmail.com. (36) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: dfisher3@mgh.harvard.edu.

Citation: Immunity 2026 Aug 13 Epub08/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594873

Tags:

Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer Spotlight 

(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M

Cell

Naara, Kochat, and Rao et al. compared the TIMEs of immunocompetent non-melanoma skin cancer (NMSC) patients and systemically immunosuppressed (IS) patients (organ transplant recipients or hematological cancer) who had reduced survival. Spatial multiomics revealed immunosuppression did not correlate with overall immune cell abundance, but with decreased numbers of intratumoral CD68+ macrophages, decreased T cell repertoire diversity, altered APC distribution, function, and cell–cell interactions, and distinct fibroblast-rich niches. Specific TIME niches showed distinct epigenetic regulation of transcription factors linked to poor immune function in IS patients.

Contributed by Katherine Turner

(1) Naara S (2) Kochat V (3) Rao X (4) Arslan E (5) Saddawi-Konefka R (6) Satpati S (7) Garbarino J (8) Anderson JL (9) Gleber-Netto FO (10) Nagarajan P (11) Kerr TD (12) Akhter S (13) Li S (14) Fodor R (15) Koyfman SA (16) Yaniv D (17) Xie T (18) Glaun M (19) Bobian M (20) Padron WI (21) Ng C (22) Gunaratne PH (23) Thevasagayampillai S (24) Migden MR (25) Abbas HA (26) Reville PK (27) Tsai KY (28) McGrail DJ (29) Wang J (30) Myers JN (31) Gross ND (32) Rai K (33) Amit M

Cell

Naara, Kochat, and Rao et al. compared the TIMEs of immunocompetent non-melanoma skin cancer (NMSC) patients and systemically immunosuppressed (IS) patients (organ transplant recipients or hematological cancer) who had reduced survival. Spatial multiomics revealed immunosuppression did not correlate with overall immune cell abundance, but with decreased numbers of intratumoral CD68+ macrophages, decreased T cell repertoire diversity, altered APC distribution, function, and cell–cell interactions, and distinct fibroblast-rich niches. Specific TIME niches showed distinct epigenetic regulation of transcription factors linked to poor immune function in IS patients.

Contributed by Katherine Turner

ABSTRACT: Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.

Author Info: (1) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) MD Anderson Epigenomics Therapy Initiative, Department of Genomic

Author Info: (1) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Otolaryngology-Head and Neck Surgery, Gleiberman Head and Neck Cancer Center, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. (6) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (8) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fonetto@mdanderson.org. (10) Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: pnagarajan@mdanderson.org. (11) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. (12) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (15) Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. (16) Department of Otolaryngology, Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel. (17) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) AtlasXomics, Pierce Laboratory, 290 Congress Ave, New Haven, CT, USA. (22) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (23) Department of Biology and Biochemistry, University of Houston Sequencing Core, University of Houston, Houston, TX, USA; Department of Molecular and Cellular Biology, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX , USA. (24) Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mrmigden@mdanderson.org. (25) Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (28) Department of Cancer Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH, USA. Electronic address: mcgraid@ccf.org. (29) Department of Bioinformatics and Computational Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) MD Anderson Epigenomics Therapy Initiative, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: krai@mdanderson.org. (33) Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Cancer Neuroscience Program, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mamit@mdanderson.org.

Citation: Cell 2026 Aug 5 Epub08/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42556334

Tags:

Dendritic cell circadian clocks shape memory CD8+ T cell differentiation

Spotlight 

(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R

Science advances | Free PMC Article

Vleeshouwers et al. showed that the time of antigen encounter determines the differentiation of antigen-specific CD8+ T cells and antiviral immunity. In mice vaccinated with mRNA-1273, active-phase (dark period for mice [nocturnal]) immunization favored progenitor-like memory CD8+ T cells and enhanced T cell-mediated protection against SARS-CoV-2 infection, whereas resting-phase vaccination skewed toward effector-memory phenotypes. The molecular circadian clock in DCs, rather than in CD8+ T cells, regulated time-of-day-dependent CD8+ T cell differentiation and function through CD70–CD27 costimulatory signaling, independent of CD28.

Contributed by Shishir Pant

(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R

Science advances | Free PMC Article

Vleeshouwers et al. showed that the time of antigen encounter determines the differentiation of antigen-specific CD8+ T cells and antiviral immunity. In mice vaccinated with mRNA-1273, active-phase (dark period for mice [nocturnal]) immunization favored progenitor-like memory CD8+ T cells and enhanced T cell-mediated protection against SARS-CoV-2 infection, whereas resting-phase vaccination skewed toward effector-memory phenotypes. The molecular circadian clock in DCs, rather than in CD8+ T cells, regulated time-of-day-dependent CD8+ T cell differentiation and function through CD70–CD27 costimulatory signaling, independent of CD28.

Contributed by Shishir Pant

ABSTRACT: Circadian rhythms regulate diverse immune processes, yet how they influence memory CD8(+) T cell differentiation remains unclear. Here, we show that the time of day of antigen encounter shapes CD8(+) T cell fate and antiviral immunity. Immunization during the active phase promotes the generation of progenitor-like memory CD8(+) T cells and enhances T cell-mediated protection upon viral challenge. Mechanistically, dendritic cell-intrinsic circadian clocks regulate expression of the costimulatory ligand CD70, thereby directing T cell differentiation. These findings uncover a dendritic cell-mediated circadian mechanism that governs memory T cell fate decisions and suggest that aligning immune priming with circadian time may be leveraged to optimize T cell immunity.

Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Alb

Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (4) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (5) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (6) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (7) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (8) Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands. (9) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Citation: Sci Adv 2026 Jul 31 12:eaeh3719 Epub07/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42536728

Tags:

Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma Spotlight 

(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) MulŽ JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S

Med | Free PMC Article

Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.

Contributed by Shishir Pant

(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) MulŽ JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S

Med | Free PMC Article

Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.

Contributed by Shishir Pant

BACKGROUND: The immunologic features of tumor-infiltrating lymphocyte (TIL) infusion products and their interactions with the tumor microenvironment that govern clinical responses in metastatic melanoma remain incompletely characterized. METHODS: We performed integrated immunophenotypic and spatial transcriptomic profiling of TIL infusion products and matched tumor microenvironments from patients treated on early-phase clinical trials. RESULTS: The durable objective response rate was 36%, with a median progression-free survival of 8 months among patients treated with TIL therapy with or without additional therapies. Responders exhibited infusion products enriched for CD8(+) T cells, stem-like memory subsets, and LAG-3-expressing CD8(+) T cells, together with enhanced peripheral TIL persistence. The abundance of infused LAG-3+ TILs correlated with tumor reactivity and prolonged progression-free survival. Prior immune checkpoint inhibitor exposure was associated with reduced CD8(+) stem cell memory T cell frequency and diminished co-stimulatory receptor expression, suggesting impaired TIL fitness. Tumors enriched for tertiary lymphoid structures and spatial immune programs characterized by antigen presentation, interferon signaling, and B cell activation were independently associated with clinical benefit. CONCLUSIONS: These findings define an integrated framework linking TIL composition and the tumor microenvironment to therapeutic response and identify potential biomarkers and biological features that may guide patient selection and optimization of TIL therapy. FUNDING: This work was funded by Iovance Biotherapeutics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence, American Cancer Society-Leo and Anne Albert Charitable Foundation Research Scholar Grant, and Melanoma SPORE (P50CA168536).

Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School

Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: lilit.karapetyan@moffitt.org. (2) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (3) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (8) Department of Molecular Biosciences, University of South Florida, Tampa, FL 33612, USA. (9) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (10) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (11) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (12) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (13) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (14) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (15) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (16) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (17) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (18) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (19) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (20) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (21) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (22) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (23) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (24) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (25) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (26) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (27) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (28) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (29) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (30) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (31) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (32) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (33) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: amod.sarnaik@moffitt.org. (34) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: matthew.beatty@moffitt.org. (35) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: shari.pilon-thomas@moffitt.org.

Citation: Med 2026 Jul 29 101231 Epub07/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42526429

Tags:

Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy

Spotlight 

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

ABSTRACT: Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compen- sated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased sMAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de rec

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de recherche Du CHUM (CRCHUM), Montréal, QC H2W1T8, Canada. 3- Centre de Recherche des Cordeliers, INSERM U1138, Equipe Labellisée – Ligue Nationale Contre le Cancer, Université Paris Cité, Sorbonne Université, 75006 Paris, France. 4- Unidad de Excelencia, Instituto de Biomedicina y Genética Molecular de Valladolid, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, 47001 Valladolid, Spain. 5- MetaGenoPolis, INRAe, Université Paris-Saclay 78350 Jouy en Josas, France. 6- Université Paris-Saclay, INSERM US23, Analyse moléculaire, modélisation et imagerie de la maladie Cancéreuse, Plateformes de Métabolomique et de Criblage Cellulaire Haut Débit, 94805 Villejuif, France. 7- Université Paris-Saclay, Gustave Roussy, U1356 Next Generation Immuno-Oncology Research, 94805 Villejuif, France

Citation: Cancer Cell July 2026

Tags:

    A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners Spotlight 

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    ABSTRACT: Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small molecule screen on primary TAMs isolated directly from GBM patient tumors, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations, and synergized with CD47 blockade ex vivo. In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA-sequencing and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-κB activation, and epigenetic priming of FcγR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM-reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San F

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San Francisco San Francisco United States. ROR: https://ror.org/043mz5j54 (4) University of California San Francisco Medical Center San Francisco United States. ROR: https://ror.org/01t8svj65 (5) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (6) Stanford University California 94305-5439, CA United States. ROR: https://ror.org/00f54p054 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (9) Stanford University Stanford University, CA United States. ROR: https://ror.org/00f54p054

    Citation: Cancer Immunol Res 2026 Jul 14 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42446904

    Tags:

    Dendritic cells control tertiary lymphoid structure development and maintenance in cancer Featured  

    (1) Mattiuz R (2) Boumelha J (3) Aerakis E (4) Le Berichel J (5) Hamon P (6) Halasz L (7) Vaidya A (8) Soong BY (9) Radkevich E (10) Kim HM (11) Park MD (12) Donne R (13) Troncoso L (14) Kaplan RA (15) Hennequin C (16) Hern‡ndez-Verdin I (17) L—pez L (18) Rentzeperis F (19) D'Souza D (20) Kaiza ME (21) MacFawn IP (22) Belabed M (23) Mestrallet G (24) Humblin E (25) Merand R (26) Hegde S (27) Lone JC (28) Ioannou G (29) Ozbey S (30) Figueiredo I (31) Tepper A (32) Merarda H (33) Serhan N (34) Schaefer MM (35) An J (36) Ohara RA (37) Nemeth E (38) Goldstein S (39) Reid AM (40) Noureddine M (41) Tabachnikova A (42) Piperno GM (43) Tsoumakidou M (44) Ahmed J (45) Polydorides AD (46) Bhardwaj N (47) Lujambio A (48) Chen Z (49) Gonzalez Kozlova E (50) Kim-Schulze S (51) Brody JD (52) Schotsaert M (53) Moussion C (54) Gnjatic S (55) Roudko V (56) Ginhoux F (57) Murphy KM (58) Sauts-Fridman C (59) Fridman WH (60) Brown BD (61) Marron TU (62) Benvenuti F (63) Cyster JG (64) Salmon H (65) Bruno TC (66) Joshi NS (67) Kamphorst AO (68) Merad M

    Science

    Mattiuz et al. assessed the role of dendritic cells in TLS formation and maintenance. Mature cDC1s were found to play essential roles, with TLS formation being dependent on maturation of cDC1s and their cross-presentation to T cells in the TDLN, followed by T cell recruitment to the tumor. Over time, maintenance of TLSs required the presence of cDC1s and cDC1 migration to CCR7 ligand-enriched stromal hubs, MHC-I and MHC-II antigen presentation to T cells, and CD40 signaling.

    (1) Mattiuz R (2) Boumelha J (3) Aerakis E (4) Le Berichel J (5) Hamon P (6) Halasz L (7) Vaidya A (8) Soong BY (9) Radkevich E (10) Kim HM (11) Park MD (12) Donne R (13) Troncoso L (14) Kaplan RA (15) Hennequin C (16) Hern‡ndez-Verdin I (17) L—pez L (18) Rentzeperis F (19) D'Souza D (20) Kaiza ME (21) MacFawn IP (22) Belabed M (23) Mestrallet G (24) Humblin E (25) Merand R (26) Hegde S (27) Lone JC (28) Ioannou G (29) Ozbey S (30) Figueiredo I (31) Tepper A (32) Merarda H (33) Serhan N (34) Schaefer MM (35) An J (36) Ohara RA (37) Nemeth E (38) Goldstein S (39) Reid AM (40) Noureddine M (41) Tabachnikova A (42) Piperno GM (43) Tsoumakidou M (44) Ahmed J (45) Polydorides AD (46) Bhardwaj N (47) Lujambio A (48) Chen Z (49) Gonzalez Kozlova E (50) Kim-Schulze S (51) Brody JD (52) Schotsaert M (53) Moussion C (54) Gnjatic S (55) Roudko V (56) Ginhoux F (57) Murphy KM (58) Sauts-Fridman C (59) Fridman WH (60) Brown BD (61) Marron TU (62) Benvenuti F (63) Cyster JG (64) Salmon H (65) Bruno TC (66) Joshi NS (67) Kamphorst AO (68) Merad M

    Science

    Mattiuz et al. assessed the role of dendritic cells in TLS formation and maintenance. Mature cDC1s were found to play essential roles, with TLS formation being dependent on maturation of cDC1s and their cross-presentation to T cells in the TDLN, followed by T cell recruitment to the tumor. Over time, maintenance of TLSs required the presence of cDC1s and cDC1 migration to CCR7 ligand-enriched stromal hubs, MHC-I and MHC-II antigen presentation to T cells, and CD40 signaling.

    ABSTRACT: Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

    Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn Schoo

    Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (11) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (17) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (18) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (21) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Department of Biology, Grove City College, Grove City, PA, USA. (22) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (23) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (24) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (25) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (26) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (27) GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. (28) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (29) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (31) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (32) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (33) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (34) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (35) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (36) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (37) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (38) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (39) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (40) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (41) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (42) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (43) Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (44) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (45) Henry D. Janowitz Division of Gastroenterology, Department of Medicine, and Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (46) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (47) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (48) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (49) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (50) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (51) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (52) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (53) Genentech, South San Francisco, CA, USA. (54) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (55) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (56) Paris-Saclay University, Gustave Roussy, INSERM U1015, Villejuif, France. (57) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (58) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (59) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (60) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (61) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (62) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (63) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (64) Institut Curie, Paris, France. (65) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (66) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (67) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Graduate Education, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (68) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

    Citation: Science 2026 Jul 16 393:eady1678 Epub07/16/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462020

    Tags:
    Close Modal

    Subscribe to our mailing list

    GDPR Marketing Permissions

    The Fritsch Foundation/ACIR.org will use the information you provide on this form to be in touch with you and to send you a weekly digest on cance immunotherapy. Click below to confirm that you want to receive the weekly digest by:

    You can change your mind at any time by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at contact@acir.org. We will treat your information with respect and will never share it with any third-parties. By clicking below, you agree that we may process your information in accordance with these terms.

    We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices here.

    Close Modal

    Small change for you. Big change for us!

    This Thanksgiving season, show your support for cancer research by donating your change.

    In less than a minute, link your credit card with our partner RoundUp App.

    Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

    All transactions are securely made through Stripe.