Journal Articles

Immune checkpoint blockade facilitates primary tumor rejection in a cDC1-independent manner without immunological memory acquisition

Spotlight 

Hitoki Arisato (1,2), Takuro Noguchi (1,3), Akihiko Shiiya (1), Yuta Toji (1), Masahiro Kashima (2), Jun Taguchi (1), Satoshi Takeuchi (1), Yasushi Shimizu (1), Hidenori Kitai (2), Kaoru Murakami (4), Jun Sakakibara-Konishi (2), Ichiro Kinoshita (5,6), Masaaki Murakami (4,7,8,9), Hirotoshi Dosaka-Akita (1), Satoshi Konno (2)

Cancer immunology, immunotherapy

Arisato et al. found that the LLC-2B2 subclone of LLC was universally rejected in ICB-treated WT mice and was also rejected in 36% of ICB-treated Batf3-/- mice. In Batf3-/- mice, rejection was dependent on CD8+ T cells primed by alternative XCR1- APCs, which upregulated costimulatory CD80, CD86, and CD40 in response to soluble factors secreted by LLC-2B2 cells. However, when mice that had cleared LLC-2B2 tumors were rechallenged, all WT mice rejected tumors, while most Batf3-/- mice did not, suggesting that cDC1s were important in establishing protective immune memory. Intratumoral injection of Flt3L-DCs restored protection from rechallenge.

Contributed by Lauren Hitchings

Hitoki Arisato (1,2), Takuro Noguchi (1,3), Akihiko Shiiya (1), Yuta Toji (1), Masahiro Kashima (2), Jun Taguchi (1), Satoshi Takeuchi (1), Yasushi Shimizu (1), Hidenori Kitai (2), Kaoru Murakami (4), Jun Sakakibara-Konishi (2), Ichiro Kinoshita (5,6), Masaaki Murakami (4,7,8,9), Hirotoshi Dosaka-Akita (1), Satoshi Konno (2)

Cancer immunology, immunotherapy

Arisato et al. found that the LLC-2B2 subclone of LLC was universally rejected in ICB-treated WT mice and was also rejected in 36% of ICB-treated Batf3-/- mice. In Batf3-/- mice, rejection was dependent on CD8+ T cells primed by alternative XCR1- APCs, which upregulated costimulatory CD80, CD86, and CD40 in response to soluble factors secreted by LLC-2B2 cells. However, when mice that had cleared LLC-2B2 tumors were rechallenged, all WT mice rejected tumors, while most Batf3-/- mice did not, suggesting that cDC1s were important in establishing protective immune memory. Intratumoral injection of Flt3L-DCs restored protection from rechallenge.

Contributed by Lauren Hitchings

ABSTRACT: Immune checkpoint blockade (ICB) provides durable therapeutic responses across multiple cancer types. Although crosstalk between T cells and conventional type 1 dendritic cells (cDC1s) is essential, the contribution of other antigen-presenting cells (APCs) to ICB-induced tumor rejection remains unclear. To address this, we show that while the majority of wild type (WT) mice rejected an immunogenic clone of Lewis lung carcinoma (LLC) following ICB, 35.7% of Batf3–/– mice, which lack the cDC1 subset, also rejected this LLC clone. ICB induced the upregulation of costimulatory markers on XCR1– APCs in the tumors and lymph nodes of Batf3–/– mice, similar to responses observed in wild-type mice. Mechanistically, conditioned culture media from LLC, but not from ICB-resistant B16F10 melanoma cells, stimulated bone marrow-derived cDC1s and cDC2s, as evidenced by the upregulation of CD40 and CD80 expression. RNA sequencing revealed that antitumor immunity-related genes were upregulated in LLC cells compared with B16F10 cells. To determine the role of cDC1-independent long-term immune memory, we rechallenged ICB-induced tumor-free mice with LLC tumors. We found that, without supplementation of cDC1s during primary rejection, Batf3–/– mice failed to spontaneously reject the rechallenged tumors. These findings demonstrate that ICB can elicit primary antitumor T cell responses against immunogenic tumors in the absence of cDC1s, whereas cDC1s are essential for the establishment of ICB-induced long-term memory. Our study underscores the importance of clinical strategies targeting both cDC1-dependent and cDC1-independent pathways to enhance the durable efficacy of ICB.

Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medici

Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan 3. Department of Medical Oncology, Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan 4. Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan 5. Department of Medical Oncology, Hokkaido University Hospital, Sapporo, Japan 6. Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan 7. Quantum immunology Team, Institute for Quantum Life science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan 8. Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan 9. Institute for Vaccine Research and Development, Hokkaido University, Sapporo 001-0021, Japan

Citation: Cancer immunology, immunotherapy 2026

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    Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy Spotlight 

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    ABSTRACT: Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmu

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmus MC Netherlands. ROR: https://ror.org/018906e22 (4) Cancer Research UK Scotland Institute United Kingdom. ROR: https://ror.org/03pv69j64 (5) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (6) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (7) Erasmus MC Rotterdam Rotterdam Netherlands. (8) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (9) Erasmus MC Rotterdam Rotterdam Netherlands. (10) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (11) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (12) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (13) University of Warsaw Poland. ROR: https://ror.org/039bjqg32 (14) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (15) Erasmus MC - Sophia Children's Hospital Rotterdam, South Holland Netherlands. ROR: https://ror.org/047afsm11 (16) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (17) Erasmus MC Rotterdam Rotterdam Netherlands. (18) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (19) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349

    Citation: Cancer Immunol Res 2026 Aug 31 Epub08/31/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42671933

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    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

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    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

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    Peripheral Th17 immune signature associates with excellent response to anti-PD1/anti-PD-L1 therapy across solid tumors Spotlight 

    (1) Li HL (2) Charmsaz S (3) Kao C (4) Pazzi C (5) Brancati M (6) Leatherman JM (7) Zhao LX (8) Arif W (9) Lee RP (10) Hernandez J (11) Gross NE (12) Ellis C (13) Thoburn C (14) Ged Y (15) Hoffman-Censits J (16) Lipson EJ (17) Baretti M (18) Chandler GS (19) Mohindra R (20) Tang L (21) Bansal S (22) Guha A (23) Jaffee EM (24) Zabransky DJ (25) Ho WJ (26) Yarchoan M (27) Nakazawa M

    Cancer immunology research

    Li et al. performed a multiyear study, prospectively analyzing peripheral immune cells and plasma cytokines from 124 patients with advanced pan-solid tumors treated with anti-PD-L1 or anti-PD-1. 30 patients achieved CR or durable PR with PFS ≥1 year, and exhibited higher levels of Th17-associated cytokines (IL-17F, -21, -23) and lower IL-8 levels at baseline and early on treatment than lesser responders. The latter showed elevated on-treatment IL-6, decreased Th17 cells, expansion of exhausted-like Th17 cells with lower lymphoid trafficking markers during early treatment, and trended toward higher on-treatment neutrophil-to-lymphocyte ratios.

    Contributed by Paula Hochman

    (1) Li HL (2) Charmsaz S (3) Kao C (4) Pazzi C (5) Brancati M (6) Leatherman JM (7) Zhao LX (8) Arif W (9) Lee RP (10) Hernandez J (11) Gross NE (12) Ellis C (13) Thoburn C (14) Ged Y (15) Hoffman-Censits J (16) Lipson EJ (17) Baretti M (18) Chandler GS (19) Mohindra R (20) Tang L (21) Bansal S (22) Guha A (23) Jaffee EM (24) Zabransky DJ (25) Ho WJ (26) Yarchoan M (27) Nakazawa M

    Cancer immunology research

    Li et al. performed a multiyear study, prospectively analyzing peripheral immune cells and plasma cytokines from 124 patients with advanced pan-solid tumors treated with anti-PD-L1 or anti-PD-1. 30 patients achieved CR or durable PR with PFS ≥1 year, and exhibited higher levels of Th17-associated cytokines (IL-17F, -21, -23) and lower IL-8 levels at baseline and early on treatment than lesser responders. The latter showed elevated on-treatment IL-6, decreased Th17 cells, expansion of exhausted-like Th17 cells with lower lymphoid trafficking markers during early treatment, and trended toward higher on-treatment neutrophil-to-lymphocyte ratios.

    Contributed by Paula Hochman

    ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed cancer care, at times generating durable partial or even complete responses in advanced cancers. However, only a minority of patients experience these "excellent" responses. Thus, there is a need for novel biomarkers that can identify those with robust clinical benefit. To address this, we prospectively collected blood samples from 124 patients with advanced and/or metastatic pan-solid tumors treated as standard of care with anti-PD1 or anti-PDL1 alone or in combination with other agents. In this cohort, 30 of 124 (24.2%) patients were classified as excellent responders (ERs), defined as experiencing a complete response or a durable partial response with progression-free survival (PFS) ³ one year. Peripheral immune cells were analyzed by Cytometry by Time-of-Flight and cytokines were analyzed using a multiplex immunoassay. At baseline and early-on-treatment, ERs had elevated concentrations of Th17-associated cytokines, IL-17F, IL-21, and IL-23, and decreased IL-8 compared to non-ERs (p<0.05). Elevated on-treatment IL-6 was also associated with non-ERs (p<0.05). High baseline IL-17F and IL-23 were associated with superior PFS, and high baseline IL-8 with inferior overall survival (p<0.05). Non-ERs demonstrated decreased proportions of Th17 cells from baseline to early-on-treatment. Regression analysis of functional markers in non-ERs showed a proliferation of exhaustion-like Th17 cells (Ki67+TIGIT+) from baseline to early-on-treatment (p<0.01), which was not present in ERs. This study identifies the Th17 pathway as a potential correlate of excellent ICI response and represents a comprehensive exploration of peripheral immune signatures associated with durable ICI benefit.

    Author Info: (1) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (2) Johns Hopkins Medicine Baltimore, MD United States. (3) Johns Hopkins Medicine Baltimore, MD United S

    Author Info: (1) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (2) Johns Hopkins Medicine Baltimore, MD United States. (3) Johns Hopkins Medicine Baltimore, MD United States. (4) Sidney Kimmel Comprehensive Cancer Center United States. (5) Johns Hopkins Medicine Baltimore, MD United States. (6) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (7) Sidney Kimmel Comprehensive Cancer Center United States. (8) Johns Hopkins University United States. (9) Johns Hopkins Medicine Baltimore, MD United States. (10) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (11) Johns Hopkins Medicine Baltimore, Maryland United States. (12) Sidney Kimmel Comprehensive Cancer Center United States. (13) Johns Hopkins Medicine Baltimore, MD United States. (14) Johns Hopkins Medicine Baltimore United States. (15) Johns Hopkins Medicine Baltimore, MD United States. (16) Johns Hopkins Medicine BALTIMORE, MD United States. (17) Johns Hopkins Medicine Baltimore, MD United States. (18) Roche (Switzerland) Basel Switzerland. (19) Roche (Switzerland) Basel Switzerland. (20) Genentech South San Francisco, CA United States. (21) Genentech San Francisco, CA United States. (22) Genentech San Francisco, CA United States. (23) Johns Hopkins University Baltimore, MD United States. (24) Johns Hopkins Medicine Baltimore, MD United States. (25) Johns Hopkins University Baltimore, MD United States. (26) Johns Hopkins Medicine Baltimore, MD United States. (27) Johns Hopkins Medicine Baltimore, MD United States.

    Citation: Cancer Immunol Res 2026 Jun 26 Epub06/26/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42360819

    Tags:

    Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

    Spotlight 

    Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

    Nature communications

    To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

    Contributed by Lauren Hitchings

    Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

    Nature communications

    To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

    Contributed by Lauren Hitchings

    ABSTRACT: Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.

    Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3

    Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3) Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (4) Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA (5) Institute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA (6) Department of Bioengineering, Rice University, Houston, TX, USA (7) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA (8) Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

    Citation: Nat com 2026

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    Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy Spotlight 

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    ABSTRACT: Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (5) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (6) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (7) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (8) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (9) University of Pittsburgh Pittsburgh, PA United States. (10) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (11) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (12) University of North Carolina Hospitals Chapel Hill, NC United States. ROR: https://ror.org/0355zfr67 (13) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Citation: Cancer Immunol Res 2026 Jul 15 Epub07/15/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42455126

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    Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial Spotlight 

    (1) Wang HH (2) Huff AL (3) Haldar SD (4) Berg M (5) Thoburn C (6) Heumann TR (7) Anders RA (8) Barrett B (9) Bever KM (10) Pishvaian MJ (11) Lee V (12) Le DT (13) Christenson ES (14) Baretti M (15) Yarchoan M (16) Laheru D (17) Thomas A (18) Durham JN (19) Nauroth JM (20) Lu J (21) Wang H (22) Jaffee EM (23) Azad NS (24) Zaidi N

    Nature communications

    Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.

    Contributed by Ute Burkhardt

    (1) Wang HH (2) Huff AL (3) Haldar SD (4) Berg M (5) Thoburn C (6) Heumann TR (7) Anders RA (8) Barrett B (9) Bever KM (10) Pishvaian MJ (11) Lee V (12) Le DT (13) Christenson ES (14) Baretti M (15) Yarchoan M (16) Laheru D (17) Thomas A (18) Durham JN (19) Nauroth JM (20) Lu J (21) Wang H (22) Jaffee EM (23) Azad NS (24) Zaidi N

    Nature communications

    Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.

    Contributed by Ute Burkhardt

    ABSTRACT: Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFN_ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.

    Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University S

    Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (6) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (13) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (14) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (15) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (16) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (17) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (19) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (22) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (23) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nilo.azad@jhu.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (24) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.

    Citation: Nat Commun 2026 Jun 23 Epub06/23/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42336869

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    Generalizable AI predicts immunotherapy outcomes across cancers and treatments Spotlight 

    (1) Shen W (2) Moon I (3) Nguyen TH (4) Li MM (5) Huang Y (6) Nair N (7) Marbach D (8) Zitnik M

    Nature medicine

    Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

    Contributed by Alex Najibi

    (1) Shen W (2) Moon I (3) Nguyen TH (4) Li MM (5) Huang Y (6) Nair N (7) Marbach D (8) Zitnik M

    Nature medicine

    Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

    Contributed by Alex Najibi

    ABSTRACT: Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio_=_4.7, P_<_0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGF_ signaling, endothelial exclusion, CD4(+) T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.

    Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biome

    Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (3) Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. (4) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (5) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (6) Roche Pharma Research and Early Development, Oncology Early Clinical Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland. (7) Computational Sciences Center of Excellence, F. Hoffmann-La Roche Ltd., Basel, Switzerland. daniel.marbach.dm1@roche.com. (8) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. marinka@hms.harvard.edu. Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA. marinka@hms.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. marinka@hms.harvard.edu. Harvard Data Science Initiative, Cambridge, MA, USA. marinka@hms.harvard.edu.

    Citation: Nat Med 2026 Jul 3 Epub07/03/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42399673

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    Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial

    Featured  

    (1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

    Nature medicine

    De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

    (1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

    Nature medicine

    De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

    ABSTRACT: Patients with estrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER+HER2- early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .

    Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franoi

    Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (3) Institut Curie, Paris, France. (4) CHU St Elisabeth, Namur, Belgium. (5) Universitaire Ziekenhuizen Leuven, Leuven, Belgium. (6) H™pital Universitaire St Luc, Brussels, Belgium. (7) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (8) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (9) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (10) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (11) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (12) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (13) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (14) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (15) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (16) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (17) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (18) ZAS Hospitals, Antwerp, Belgium. Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia. (19) Iridium Netwerk, Antwerp, Belgium. University of Antwerp, Antwerp, Belgium. (20) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (21) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (22) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (23) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (24) Institut Curie, Paris, France. (25) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium.

    Citation: Nat Med 2026 Jun 25 Epub06/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350643

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