Journal Articles

Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer

Spotlight 

(1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

Cancer cell

Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

Contributed by Shishir Pant

(1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

Cancer cell

Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

Contributed by Shishir Pant

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8(+) T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8(+) T cells or tumor cell MHC expression but instead requires IFN_-producing CD4(+) T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4(+) T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4(+) T cell-IFN_ axis could be efficacious in PDAC.

Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farbe

Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (2) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School Program in Virology, Boston, MA, USA. (3) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (6) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (7) Brookline High School, Brookline, MA, USA. (8) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (9) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (10) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (11) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (12) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (13) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (14) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (16) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (17) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (18) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (20) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (21) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (22) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, MA, USA. (24) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (27) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (28) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (30) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (31) Bristol Myers Squibb, Princeton, NJ, USA. (32) Bristol Myers Squibb, Princeton, NJ, USA. (33) Bristol Myers Squibb, Princeton, NJ, USA. (34) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (35) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (36) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

Citation: Cancer Cell 2026 May 7 Epub05/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102812

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Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways Spotlight 

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

ABSTRACT: Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αEβ7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Cent

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 20080, China; Breast and Thyroid Surgery Department, General Surgery Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (2) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (3) Department of Breast, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, No. 910 Hengshan Road, Shanghai, China. (4) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (5) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (6) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (7) Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 21500, China. (8) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (9) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (10) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (11) Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China. (12) Cancer Center, Faculty of Health Science, University of Macau, Macau 999078, China. (13) State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. (14) Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. (15) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (16) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (17) Department of Surgery, The Chinese University of Hong Kong Prince of Wales Hospital, Shatin 999077, Hong Kong SAR, China. (18) State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai 200031, China. (19) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. (20) Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (21) Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China. (22) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (23) Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: gem23@163.com. (24) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: drtaozhh@126.com. (25) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: liuwenting1015@163.com. (26) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. Electronic address: whx365@126.com.

Citation: Cancer Cell 2026 May 7 Epub05/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102811

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Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function Spotlight 

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

ABSTRACT: Regulatory T cells (T(reg) cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring T(reg) cell-specific gene expression and stable suppressive functions, yet Foxp3's contribution to this epigenetic identity remains unclear. Leveraging Foxp3-transduced conventional T cells as a gain-of-function probe in mice, we identified a previously unrecognized subset that acquires endogenous Foxp3 expression, T(reg) cell-like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in T(reg) cells but impaired in Foxp3-mutant T(reg)-like cells, demonstrating a Foxp3 requirement. Induction of endogenous Foxp3 expression in vivo required reduced AKT-mTOR signaling and Foxp3-dependent engagement of STAT5 and nuclear factor _B (NF-_B). Temporal chromatin profiling revealed stepwise Foxp3-driven regulatory programs, including a core program shared across T(reg) cell subsets and effector-specific programs, both associated with NF-_B activity and Foxp3 binding. Thus, Foxp3 integrates cell-intrinsic and environmental contexts to drive epigenetic programs defining T(reg) cell identities and functions, with implications for Foxp3-based therapies.

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduat

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (3) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (4) Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (5) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (6) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (7) Department of Applied Genomics, Kazusa DNA Research Institute, Chiba 292-0818, Japan. (8) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. (9) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan. (10) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Citation: Sci Immunol 2026 May 11:eaed2111 Epub05/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066061

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Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality

Spotlight 

(1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

Science

Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

Contributed by Paula Hochman

(1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

Science

Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

Contributed by Paula Hochman

ABSTRACT: The generation of effector CD8(+) T cells (T(EFF)) requires activation of nave CCR7(+) T cells (T(N)) by dendritic cells (DCs) in lymphoid tissue. How T(N)-DC interaction duration and signal integration are controlled remains unclear. In this study, we show that lymphoid stroma-secreted CCR7 ligands limit interaction duration by progressively inducing CD8(+) T cell release from DCs. At late interaction stages, CCR7 ligands relocalize the F-actin regulator DOCK2 away from the DC interface, permitting T cell detachment, proliferation onset, and acquisition of cytotoxicity. Disruption of CCR7 signaling causes prolonged T cell-DC contacts and produces dysfunctional T(EFF) with elevated inhibitory receptors, reduced antimicrobial activity, and impaired recall responses. Stromal chemokines therefore act as critical regulators of T cell priming by DCs, preserving CD8(+) effector function during acute and memory phases.

Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribo

Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (3) Department of Biomedicine, University of Basel, Basel, Switzerland. (4) Department of Biology, University of Fribourg, Fribourg, Switzerland. (5) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (7) Institute of Neuropathology, UniversitŠtsklinikum Erlangen, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (8) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (9) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (10) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (11) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (12) Department of Biomedicine, University of Basel, Basel, Switzerland. (13) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (14) Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland. Department of Urology, Inselspital University Hospital, Bern, Switzerland. Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Department of Surgery, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. (15) Department of Biology, University of Fribourg, Fribourg, Switzerland. (16) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (17) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland.

Citation: Science 2026 Apr 30 392:eadq2080 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42060746

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The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion Spotlight 

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

ABSTRACT: The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical O

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (3) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (5) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (6) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (7) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (8) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (9) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (11) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (12) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (13) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (14) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. (15) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (16) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (17) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (18) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (19) Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, USA. (20) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (21) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (22) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (23) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (24) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (25) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (26) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (27) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (28) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (29) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.

Citation: Dev Cell 2026 Apr 28 Epub04/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42055006

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Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity

Spotlight 

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

ABSTRACT: A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krppel-like factor 2 (KLF2) as a top TF driving CX3CR1(+) effector-like exhausted cell (Tex(eff-like)) differentiation. Overexpression of KLF2 converted CX3CR1_ cells into Tex(eff-like) cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8(+) T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Tex(eff-like) program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, X

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (2) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (3) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (4) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (5) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (6) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (7) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (8) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (9) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (10) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (11) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (13) Department of Pharmacy, Xiamen Medical College, Xiamen, Fujian 361023, China. (14) Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. (15) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (16) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (17) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (19) School of Medicine, Xiamen University, South Xiang'an Road, Xiamen, Fujian 361102, China. (20) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (21) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (22) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (23) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: honglinghuang@xmu.edu.cn.

Citation: Immunity 2026 Apr 27 Epub04/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42049034

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Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity Spotlight 

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

ABSTRACT: Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (AT(EVs)) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. AT(EV)-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EV(DNA)), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by AT(EVs) disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EV(DNA) encoding APP genes. DNase treatment removes most AT-EV(DNA), abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, AT(EVs) hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by AT(EVs) that boosts APP and anti-tumor immunity while limiting autoimmunity.

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. (2) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (5) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Systems Biology, Columbia University, New York, NY, USA. (8) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. (10) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linkšping University, Linkšping, Sweden. (11) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (12) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (13) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (14) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (15) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (16) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (17) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (19) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (20) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (21) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (23) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (24) Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA. (25) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (27) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Pathology, University of California, San Diego, La Jolla, CA, USA. (29) Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium. (30) Laboratory of Biology of Tumor and Development, UniversitŽ de Lige, Lige, Belgium. (31) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (32) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (33) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA. (34) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (35) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (37) Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (38) Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA. (39) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (40) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (41) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. (42) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (43) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: haz2005@med.cornell.edu. (44) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: irm2224@med.cornell.edu. (45) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

Citation: Cancer Cell 2026 Apr 30 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066762

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Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection Spotlight 

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

ABSTRACT: Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc_R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc_R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc_R III or inhibitory Fc_R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc_R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc_R-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. CHA Biotech, CHA Bio Complex, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California, San Francisco, CA 94143. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (8) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (9) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (13) Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (14) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (16) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322. (17) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA (18) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (20) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322.

Citation: Proc Natl Acad Sci U S A 2026 Apr 14 123:e2427192123 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41950082

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Debio 1562M CD37-targeting ADC is highly active and well tolerated in preclinical models of AML and MDS Spotlight 

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

(1) Marx L (2) Hue-Perron J (3) Monjardet A (4) Vigano S (5) Chardonnens C (6) Morse K (7) Artiga E (8) Roubaudi-Fraschini MC (9) Wuttke R (10) Colombo R (11) Larkin K (12) Ivanschitz L

Cell reports. Medicine

Addressing the need for superior toxin delivery and safety for AML and MDS therapies, Marx et al. developed Debio 1562M, a next-generation ADC targeting CD37, which is broadly expressed on AML and MDS blasts. Debio 1562M (with a drug [DM1]-to-naratuximab ratio of 8, and a cathepsin-cleavable linker) was efficiently internalized and killed blast cells in blood and bone marrow. In multiple models, Debio 1562M outperformed standard-of-care treatments, and demonstrated broad and efficient anti-leukemic activity on all AML subtypes. Compared to 1st generation CD37 ADC, Debio 1562M had an improved toxicity profile in mice, and is in a phase 1 trial for r/r AML and high-risk MDS.

Contributed by Katherine Turner

ABSTRACT: The leukocyte antigen CD37 is broadly expressed on acute myeloid leukemia (AML) blasts and associated with poor prognosis. We demonstrate that myelodysplastic syndrome (MDS) cells also express CD37, and both AML and MDS cells have favorable internalization properties of this receptor. Debio 1562M is a next-generation antibody-drug conjugate (ADC) that targets CD37 and is optimized to deliver more toxins to tumor cells than the first-generation ADC Debio 1562, while maintaining a good safety profile. Preclinically, Debio 1562M showed robust anti-leukemic activity in AML and MDS primary samples and in AML xenograft models, irrespective of disease stage or genotype. Debio 1562M was able to target leukemic stem cells in vitro and significantly decrease tumor burden in blood and bone marrow, resulting in survival prolongation compared with standard-of-care treatments. These data demonstrate that CD37 is a relevant target for both indications and that Debio 1562M is a promising therapeutic candidate.

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausann

Author Info: (1) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (2) Debiopharm International SA, 1006 Lausanne, Switzerland. (3) Debiopharm International SA, 1006 Lausanne, Switzerland. (4) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (5) Debiopharm Research and Manufacturing SA, 1920 Martigny, Switzerland. (6) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (7) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (8) Debiopharm International SA, 1006 Lausanne, Switzerland. (9) Debiopharm International SA, 1006 Lausanne, Switzerland. (10) Debiopharm International SA, 1006 Lausanne, Switzerland. (11) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. (12) Debiopharm International SA, 1006 Lausanne, Switzerland. Electronic address: lisa.ivanschitz@debiopharm.com.

Citation: Cell Rep Med 2026 Apr 20 102749 Epub04/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42013843

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mRNA vaccines engage unconventional pathways in CD8+ T cell priming

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(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

ABSTRACT: Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8(+) T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens(1-4). However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8(+) T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8(+) T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8(+) T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8(+) T cells against antigens not encoded by the vaccine.

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis Sc

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. (3) Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (6) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (7) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (8) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (9) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (10) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (11) Innovac Therapeutics, Cambridge, MA, USA. (12) Innovac Therapeutics, Cambridge, MA, USA. (13) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. (14) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (15) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (16) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (17) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. (18) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. kmurphy@wustl.edu.

Citation: Nature 2026 Apr 15 Epub04/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41986715

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