Journal Articles

T cell priming by high avidity neoantigens in lymph nodes augments adoptive immunotherapy Spotlight 

(1) Wittling MC (2) Rivera Reyes AM (3) Wyatt MM (4) Cole AC (5) Smith AS (6) Rangel Rivera GO (7) Carmouche JH (8) Diatikar KG (9) Ruffin AT (10) Ware MB (11) Bennett FJ (12) Dwyer CJ (13) Pihl RMF (14) Kumaresan S (15) Lesinski GB (16) Paulos CM (17) Knochelmann HM

Cancer immunology research

To study how neoantigen avidity impacts T cell function in adoptive cell therapy (ACT), Wittling et al. compared antitumor responses of naive transgenic pmel-1 CD8+ T cells transferred into a B16F10 melanoma model expressing either low-avidity gp100 (wild-type) or a high-avidity mutant gp100 (EGS to KVP) neoantigen. Compared to wild-type, high-avidity KVP neoantigen was sufficient to activate naive CD8+ T cells, leading to enhanced cytokine production, increased effector function, sustained persistence, robust tumor regression, and long-term immunity, even in the absence of host T and B cells. Early lymph node trafficking was essential for ACT efficacy.

Contributed by Katherine Turner

(1) Wittling MC (2) Rivera Reyes AM (3) Wyatt MM (4) Cole AC (5) Smith AS (6) Rangel Rivera GO (7) Carmouche JH (8) Diatikar KG (9) Ruffin AT (10) Ware MB (11) Bennett FJ (12) Dwyer CJ (13) Pihl RMF (14) Kumaresan S (15) Lesinski GB (16) Paulos CM (17) Knochelmann HM

Cancer immunology research

To study how neoantigen avidity impacts T cell function in adoptive cell therapy (ACT), Wittling et al. compared antitumor responses of naive transgenic pmel-1 CD8+ T cells transferred into a B16F10 melanoma model expressing either low-avidity gp100 (wild-type) or a high-avidity mutant gp100 (EGS to KVP) neoantigen. Compared to wild-type, high-avidity KVP neoantigen was sufficient to activate naive CD8+ T cells, leading to enhanced cytokine production, increased effector function, sustained persistence, robust tumor regression, and long-term immunity, even in the absence of host T and B cells. Early lymph node trafficking was essential for ACT efficacy.

Contributed by Katherine Turner

ABSTRACT: Adoptive transfer of T lymphocytes specific for tumor-associated neoantigens can elicit immunity against solid tumors in patients. However, how these antigens impact T cell function, effector differentiation, and persistence remains unclear. We examined how an identical CD8+ T cell product was shaped by melanoma expressing either a low-avidity tumor-associated antigen or high-avidity neoantigen, and kinetically profiled T cell differentiation in these two contexts across host tissues. High-avidity neoantigen expression was sufficient to activate naïve CD8+ T cells - leading to robust tumor regression and long-term protective immunity upon tumor rechallenge. Mechanistically, transferred naïve CD8+ T cells reacting to high-avidity neoantigen exhibited enhanced cytokine production, heightened effector function, and sustained persistence compared to the low-avidity wild-type tumors. Antitumor activity to these high-avidity tumors was preserved even in the absence of functional host T and B lymphocytes, and early lymph node trafficking was found to be essential for ACT efficacy. Expanded effector or stem-memory T cells were compared to the naïve pmel-1 T cell product. Stem-memory but not effector-memory cells exhibited similar antitumor efficacy and lymph node trafficking patterns to the naïve cells in mice with high-avidity neoantigen tumors. These findings highlight how differential tumor antigens shape divergent cellular fate and uncover a critical role of T cell trafficking in lymph nodes in shaping high-avidity neoantigen-specific antitumor responses.

Author Info: (1) Emory University, Atlanta, GA, United States. (2) Emory University, Atlanta, GA, United States. (3) Emory University, Atlanta, GA, United States. (4) Emory University, Atlanta,

Author Info: (1) Emory University, Atlanta, GA, United States. (2) Emory University, Atlanta, GA, United States. (3) Emory University, Atlanta, GA, United States. (4) Emory University, Atlanta, GA, United States. (5) Emory University, Atlanta, Georgia, United States. (6) Medical University of South Carolina, Charleston, SC, United States. (7) Emory University, Atlanta, GA, United States. (8) Emory University, Atlanta, GA, United States. (9) Emory University, Atlanta, GA, United States. (10) Emory University, Atlanta, GA, United States. (11) Emory University, Atlanta, GA, United States. (12) Werewolf Therapeutics, Watertown, MA, United States. (13) Lumicks, Amsterdam, Netherlands. (14) Emory University, Atlanta, GA, United States. (15) Winship Cancer Institute, Atlanta, GA, United States. (16) Emory University, Atlanta, GA, United States. (17) Stanford University, Palo Alto, CA, United States.

Citation: Cancer Immunol Res 2025 Dec 5 Epub12/05/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41348132

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Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering Spotlight 

(1) He J (2) Zhang C (3) Liang C (4) Xue W (5) Li Y (6) Dai L (7) Liu C (8) Zhuang WR (9) Ma X (10) Cheng R (11) Lei Y (12) Nie W (13) Xie HY

Cell reports. Medicine

He et al. engineered an i.v.-delivered nanoparticle containing a plasmid PαCD3&LIGHT, in which a TERT promoter drives tumor-restricted αCD3 and LIGHT expression to reprogram T cell immunity in the TME of immune-cold solid tumors. LIGHT induced HEV formation, chemokine secretion, ECM remodeling, and T cell infiltration, while αCD3 established artificial immunological synapses, amplified TCR signaling, and reinvigorated exhausted T cells. PαCD3&LIGHT suppressed multiple immune-cold solid tumor mouse models and enhanced ICB and CAR T cell efficacy, without obvious systemic toxicity. A humanized construct enhanced human CAR T activity, without systemic toxicity.

Contributed by Shishir Pant

(1) He J (2) Zhang C (3) Liang C (4) Xue W (5) Li Y (6) Dai L (7) Liu C (8) Zhuang WR (9) Ma X (10) Cheng R (11) Lei Y (12) Nie W (13) Xie HY

Cell reports. Medicine

He et al. engineered an i.v.-delivered nanoparticle containing a plasmid PαCD3&LIGHT, in which a TERT promoter drives tumor-restricted αCD3 and LIGHT expression to reprogram T cell immunity in the TME of immune-cold solid tumors. LIGHT induced HEV formation, chemokine secretion, ECM remodeling, and T cell infiltration, while αCD3 established artificial immunological synapses, amplified TCR signaling, and reinvigorated exhausted T cells. PαCD3&LIGHT suppressed multiple immune-cold solid tumor mouse models and enhanced ICB and CAR T cell efficacy, without obvious systemic toxicity. A humanized construct enhanced human CAR T activity, without systemic toxicity.

Contributed by Shishir Pant

ABSTRACT: We engineer a tumor-targeted genetic plasmid vector (P(_CD3&LIGHT)) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (_CD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. _CD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8(+) T cells and driving sustained immunity. Concurrently, _CD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.

Author Info: (1) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (2) State Key Laboratory of Crop Gene Resources and Breeding, Institute of Crop Sciences, Chines

Author Info: (1) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (2) State Key Laboratory of Crop Gene Resources and Breeding, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China. (3) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (4) School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China. (5) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China. (6) Department of Respiratory and Digestive, Qian'an Yanshan Hospital, Tangshan 064400, China. (7) Department of Otorhinolaryngology, Qian'an Yanshan Hospital, Tangshan 064400, China. (8) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China. (9) School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China. (10) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. (11) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China. (12) School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address: victornia@bit.edu.cn. (13) State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China; Peking University Ningbo Institute of Marine Medicine, Ningbo 315832, China. Electronic address: hyanxie@bjmu.edu.cn.

Citation: Cell Rep Med 2025 Dec 16 6:102510 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41406950

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A universal boosting strategy for adoptive T cell therapy using a paired vaccine/chimeric antigen receptor Spotlight 

(1) Burchett R (2) Morris CG (3) Ishak M (4) Serniuck NJ (5) Cummings DT (6) Baker CL (7) Marius R (8) Kazdhan N (9) Silvestri CM (10) Bell J (11) Lichty BD (12) Walsh SR (13) Wan Y (14) Hammill JA (15) Bramson JL

Cancer immunology research

Burchett et al. investigated various vaccine-based approaches to boost the effects of CMV gp33-targeted (P14) TCR T cells in a solid tumor model, particularly focused on a CAR/vaccine combination targeting a “universal” surrogate epitope (BCMA). A VSV-based vaccine expressing surface BCMA (but not a secreted BCMA-Ig-Fc) expanded the BCMACAR_P14 T cells at day 5, but persistence was very limited. Early tumor responses and a survival benefit, but no cures, were observed. VSV-induced IFN-I limited gp33 expression, but blocking IFNAR1 had minimal impact on persistence. Gp33-stimulation of P14 cells through the TCR enhanced persistence, induced endogenous T cells, and eliminated gp33+ tumor cells.

Contributed by Ed Fritsch

(1) Burchett R (2) Morris CG (3) Ishak M (4) Serniuck NJ (5) Cummings DT (6) Baker CL (7) Marius R (8) Kazdhan N (9) Silvestri CM (10) Bell J (11) Lichty BD (12) Walsh SR (13) Wan Y (14) Hammill JA (15) Bramson JL

Cancer immunology research

Burchett et al. investigated various vaccine-based approaches to boost the effects of CMV gp33-targeted (P14) TCR T cells in a solid tumor model, particularly focused on a CAR/vaccine combination targeting a “universal” surrogate epitope (BCMA). A VSV-based vaccine expressing surface BCMA (but not a secreted BCMA-Ig-Fc) expanded the BCMACAR_P14 T cells at day 5, but persistence was very limited. Early tumor responses and a survival benefit, but no cures, were observed. VSV-induced IFN-I limited gp33 expression, but blocking IFNAR1 had minimal impact on persistence. Gp33-stimulation of P14 cells through the TCR enhanced persistence, induced endogenous T cells, and eliminated gp33+ tumor cells.

Contributed by Ed Fritsch

ABSTRACT: Vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing vaccines to boost adoptively transferred tumour-reactive T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model wherein murine T cells expressing a TCR specific for antigen on syngeneic tumours were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumour-specific T cells with paired vesicular stomatitis virus (VSV) vaccines was associated with robust T cell expansion and delayed tumour progression in the absence of prior lymphodepletion. CAR-T cell expansion and antitumour function was further enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells during vaccination to achieve long-term tumour control.

Author Info: (1) McMaster University, Hamilton, ON, Canada. (2) McMaster University, Hamilton, Ontario, Canada. (3) McMaster University, Hamilton, Ontario, Canada. (4) McMaster University, Hami

Author Info: (1) McMaster University, Hamilton, ON, Canada. (2) McMaster University, Hamilton, Ontario, Canada. (3) McMaster University, Hamilton, Ontario, Canada. (4) McMaster University, Hamilton, ON, Canada. (5) McMaster University, Hamilton, Ontario, Canada. (6) McMaster University, Hamilton, ON, Canada. (7) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (8) McMaster University, Hamilton, Ontario, Canada. (9) McMaster University, Hamilton, ON, Canada. (10) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (11) McMaster University, Hamilton, Ontario, Canada. (12) McMaster University, Hamilton, Canada. (13) McMaster University, Hamilton, Ontario, Canada. (14) McMaster University, Hamilton, ON, Canada. (15) McMaster University, Hamilton, Ontario, Canada.

Citation: Cancer Immunol Res 2025 Dec 8 Epub12/08/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41359369

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Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity Spotlight 

(1) Jin Y (2) Yang Z (3) Li Z (4) Ding Z (5) Zhang X (6) Zeng H (7) Fang L (8) Shi Y (9) Xing P (10) Liu W (11) Chen H (12) Jing C (13) Cao G

Cell reports. Medicine

In participants in the UK Biobank and a US National Survey, inflammation scores increased with age and in cases of chronic health conditions, and correlated positively with cancer incidence and mortality. 8 cancers were identified as inflammation-related, and aerobic physical activity correlated negatively with inflammation and cancer mortality. In C57 mice and Syrian hamsters, exercise impacted expression of genes associated with senescence, innate/adaptive immunity, and apoptosis, and boosted anti-inflammatory serum cytokines, compared to non-exercised controls. Mki67+ B and T cells had particularly high senescence-related gene scores.

Contributed by Alex Najibi

(1) Jin Y (2) Yang Z (3) Li Z (4) Ding Z (5) Zhang X (6) Zeng H (7) Fang L (8) Shi Y (9) Xing P (10) Liu W (11) Chen H (12) Jing C (13) Cao G

Cell reports. Medicine

In participants in the UK Biobank and a US National Survey, inflammation scores increased with age and in cases of chronic health conditions, and correlated positively with cancer incidence and mortality. 8 cancers were identified as inflammation-related, and aerobic physical activity correlated negatively with inflammation and cancer mortality. In C57 mice and Syrian hamsters, exercise impacted expression of genes associated with senescence, innate/adaptive immunity, and apoptosis, and boosted anti-inflammatory serum cytokines, compared to non-exercised controls. Mki67+ B and T cells had particularly high senescence-related gene scores.

Contributed by Alex Najibi

ABSTRACT: The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67(+) immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3(+) immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals. These findings link exercise training to cancer risk reduction by alleviating inflammation, decreasing immunosenescence, and improving the reservoirs of overall immunity for cancer prevention.

Author Info: (1) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical Uni

Author Info: (1) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (2) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (3) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (4) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (5) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (6) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (7) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (8) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (9) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (10) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (11) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (12) Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (13) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. Electronic address: gcao@smmu.edu.cn.

Citation: Cell Rep Med 2025 Dec 16 6:102484 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41406938

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Lymphodepleting chemotherapy potentiates neoantigen-directed T cell therapy by enhancing antigen presentation Spotlight 

(1) Sagie S (2) Babu T (3) Weller C (4) Tabachnik C (5) Livneh I (6) Quast NP (7) Gumpert N (8) Shomuradova A (9) Raybould MI (10) Levy R (11) Malko D (12) Alfia A (13) Ben Lulu T (14) Alon M (15) Herrera F (16) Kutuzov M (17) Zerbib M (18) Greenberg P (19) Wasserman-Bartov T (20) Benedek G (21) Levin Y (22) Stossel C (23) Kamer I (24) Golan T (25) Oren R (26) Shmueli M (27) Bartok O (28) Bar J (29) Cohen J (30) Dushek O (31) Deane CM (32) Samuels Y

Cell reports. Medicine

Sagie and Babu et al. showed that antigen-specific killing of tumors by T cells expressing T104 – a novel, potent TCR specific for the HLA-A*03:01-restricted KRAS.G12V neoantigen – and by other neoantigen-specific T cells, TILs, and T cell-engager Abs, was boosted by lymphodepleting Cy-Flu chemotherapy-treated cultures at concentrations that minimized direct tumor cytotoxicity. Sublethal chemotherapy elevated immunoproteasome activity and HLA-I surface expression to increase the number, diversity, and hydrophobicity of therapeutically relevant neoantigen peptides for presentation in vitro and in tumors implanted s.c. into immunodeficient mice.

Contributed by Paula Hochman

(1) Sagie S (2) Babu T (3) Weller C (4) Tabachnik C (5) Livneh I (6) Quast NP (7) Gumpert N (8) Shomuradova A (9) Raybould MI (10) Levy R (11) Malko D (12) Alfia A (13) Ben Lulu T (14) Alon M (15) Herrera F (16) Kutuzov M (17) Zerbib M (18) Greenberg P (19) Wasserman-Bartov T (20) Benedek G (21) Levin Y (22) Stossel C (23) Kamer I (24) Golan T (25) Oren R (26) Shmueli M (27) Bartok O (28) Bar J (29) Cohen J (30) Dushek O (31) Deane CM (32) Samuels Y

Cell reports. Medicine

Sagie and Babu et al. showed that antigen-specific killing of tumors by T cells expressing T104 – a novel, potent TCR specific for the HLA-A*03:01-restricted KRAS.G12V neoantigen – and by other neoantigen-specific T cells, TILs, and T cell-engager Abs, was boosted by lymphodepleting Cy-Flu chemotherapy-treated cultures at concentrations that minimized direct tumor cytotoxicity. Sublethal chemotherapy elevated immunoproteasome activity and HLA-I surface expression to increase the number, diversity, and hydrophobicity of therapeutically relevant neoantigen peptides for presentation in vitro and in tumors implanted s.c. into immunodeficient mice.

Contributed by Paula Hochman

ABSTRACT: Adoptive cell therapy (ACT) targeting tumor-specific antigens holds promise for solid tumors, but limited neoantigen presentation remains a key barrier to efficacy. Here, we identify and characterize a T cell receptor (TCR), T104, for the KRAS.G12V mutation, a prevalent neoantigen in colorectal, lung, and pancreatic cancers. TCR-T104 selectively recognizes and kills KRAS.G12V-expressing tumor cells. Combining T cell therapy with lymphodepleting chemotherapy significantly enhances tumor cell killing, particularly by TCR-T cells, tumor-infiltrating lymphocytes (TILs), and T cell engager antibodies across multiple cancer types and target antigens. Mechanistically, chemotherapy upregulates immunoproteasome activity and human leukocyte antigen (HLA)-I surface expression. HLA-immunopeptidome analyses reveal that chemotherapy remodels the antigenic landscape across tumor cell lines and in vivo models, increasing peptide abundance and hydrophobicity while altering proteasomal cleavage preferences. These findings establish a synergistic role for chemotherapy in enhancing neoantigen presentation and T cell-mediated tumor recognition and suggest that fine-tuning these regimens could improve ACT efficacy, particularly in tumors with low-abundance neoantigens.

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel. (2) Departm

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (3) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (5) Rappaport Technion Cancer Research center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel; Institute of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel. (6) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (7) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (8) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (9) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (10) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (11) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (12) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel. (13) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (14) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (16) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (17) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (18) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (19) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (20) Faculty of Medicine, Hadassah Hebrew-University Medical Center, Jerusalem 91120, Israel. (21) INCPM, Weizmann Institute of Science, Rehovot 7610001, Israel. (22) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (23) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (24) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (25) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (26) Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. (27) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (28) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (29) Sharett Institute of Oncology, Hadassah Cancer Research Institute and The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. (30) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (31) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (32) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: yardena.samuels@weizmann.ac.il.

Citation: Cell Rep Med 2025 Dec 16 6:102506 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41406943

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HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion Spotlight 

(1) Chemla Y (2) Itzhaki O (3) Melamed S (4) Weller C (5) Sade Y (6) Manich P (7) Reshef K (8) Xenidis N (9) Maliah A (10) Levy G (11) Parikh R (12) Bartok O (13) Levy O (14) Tal I (15) Aziel G (16) Nissani A (17) Yunger S (18) Likonen D (19) Kliminsky V (20) Golan T (21) Capron C (22) Ace V (23) Levy R (24) Rasoulouniriana D (25) Eyal Z (26) Barzilay Y (27) Balaban R (28) Khateeb A (29) Khosravi R (30) Grau A (31) Ziv T (32) Greenberg P (33) Netanely D (34) Vaknin H (35) Wu X (36) Amitay Y (37) Brenner R (38) Mart’nez G—mez JM (39) Hershkovitz D (40) Yardeni T (41) Zemser-Werner V (42) Kobiler O (43) Friedmann Y (44) Bassan D (45) Shamir R (46) Eisenbach L (47) Santana-Magal N (48) Milyavsky M (49) Eisenberg G (50) Keren L (51) Cohen M (52) Gur D (53) Barak B (54) Lotem M (55) Sprinzak D (56) Greenberger S (57) Fisher D (58) Besser MJ (59) Khaled M (60) Close P (61) Shapira R (62) Apcher S (63) Madi A (64) Levesque MP (65) Rapino F (66) Carmi Y (67) Parikh S (68) Samuels Y (69) Levy C

Cell

Chemla et al. demonstrated that melanosomes, large extracellular vesicles secreted by melanoma cells, carry MHC-I molecules as active mediators for immune evasion. Melanosomes present tumor-associated antigens and neoantigens that directly engage CD8+ T cell receptors and compete with tumor cells for TCR binding, diverting antigen recognition away from malignant cells. Melanosome–TCR engagement induced incomplete activation, mitochondrial dysfunction, and apoptosis in CD8+ T cells. Inhibiting melanosome secretion restored CD8+ T cell infiltration and restrained tumor growth in the B16F10 melanoma model.

Contributed by Shishir Pant

(1) Chemla Y (2) Itzhaki O (3) Melamed S (4) Weller C (5) Sade Y (6) Manich P (7) Reshef K (8) Xenidis N (9) Maliah A (10) Levy G (11) Parikh R (12) Bartok O (13) Levy O (14) Tal I (15) Aziel G (16) Nissani A (17) Yunger S (18) Likonen D (19) Kliminsky V (20) Golan T (21) Capron C (22) Ace V (23) Levy R (24) Rasoulouniriana D (25) Eyal Z (26) Barzilay Y (27) Balaban R (28) Khateeb A (29) Khosravi R (30) Grau A (31) Ziv T (32) Greenberg P (33) Netanely D (34) Vaknin H (35) Wu X (36) Amitay Y (37) Brenner R (38) Mart’nez G—mez JM (39) Hershkovitz D (40) Yardeni T (41) Zemser-Werner V (42) Kobiler O (43) Friedmann Y (44) Bassan D (45) Shamir R (46) Eisenbach L (47) Santana-Magal N (48) Milyavsky M (49) Eisenberg G (50) Keren L (51) Cohen M (52) Gur D (53) Barak B (54) Lotem M (55) Sprinzak D (56) Greenberger S (57) Fisher D (58) Besser MJ (59) Khaled M (60) Close P (61) Shapira R (62) Apcher S (63) Madi A (64) Levesque MP (65) Rapino F (66) Carmi Y (67) Parikh S (68) Samuels Y (69) Levy C

Cell

Chemla et al. demonstrated that melanosomes, large extracellular vesicles secreted by melanoma cells, carry MHC-I molecules as active mediators for immune evasion. Melanosomes present tumor-associated antigens and neoantigens that directly engage CD8+ T cell receptors and compete with tumor cells for TCR binding, diverting antigen recognition away from malignant cells. Melanosome–TCR engagement induced incomplete activation, mitochondrial dysfunction, and apoptosis in CD8+ T cells. Inhibiting melanosome secretion restored CD8+ T cell infiltration and restrained tumor growth in the B16F10 melanoma model.

Contributed by Shishir Pant

ABSTRACT: While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8(+) T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8(+) T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.

Author Info: (1) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (2) Department of Human Genetics and Bi

Author Info: (1) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (2) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (3) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (6) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (7) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (8) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (9) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (10) Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. (11) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (12) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (13) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (14) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (15) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (16) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (17) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. (18) Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel. (19) Department of Dermatology, Sheba Medical Center, Ramat Gan, Israel. (20) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (21) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. (22) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (23) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (24) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (25) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (26) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (27) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (28) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (29) Single Cell Genomics Core, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (30) Biomedical Core Facility, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. (31) Smoler Proteomics Center, Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion-Israel Institute of Technology, Haifa, Israel. (32) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (33) Blavatnik School of Computer Science and Artificial Intelligence, Tel Aviv University, Tel Aviv, Israel. (34) Institute of Oncology, E. Wolfson Medical Center, Holon, Israel. (35) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (36) Department of Molecular Cell Biology, Weizmann Institute of Science, Tel Aviv, Israel. (37) Institute of Oncology, E. Wolfson Medical Center, Holon, Israel. (38) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. (39) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (40) Metabolic Center, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. (41) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (42) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (43) Bio-Imaging Unit, Hebrew University, Jerusalem 91904, Israel. (44) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (45) Blavatnik School of Computer Science and Artificial Intelligence, Tel Aviv University, Tel Aviv, Israel. (46) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (47) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (48) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. (49) Hadassah Cancer Research Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel. (50) Department of Molecular Cell Biology, Weizmann Institute of Science, Tel Aviv, Israel. (51) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (52) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. (53) Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; The School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel. (54) Hadassah Cancer Research Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel. (55) School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (56) Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (57) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (58) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel; Department of Clinical Microbiology and Immunology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Samueli Integrative Pioneering Institute and Davidoff Center, Rabin Medical Center, Petach Tikva, Israel; Felsenstein Cancer Research Center, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. (59) Gustave Roussy Cancer Campus, INSERM U1015, Universite Paris-Saclay, 114 rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: mehdi.khaled@gustaveroussy.fr. (60) Laboratory of Cancer Signaling, GIGA Institute, University of Lige, Lige, Belgium. Electronic address: pierre.close@uliege.be. (61) Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Ramat Gan 52621, Israel. Electronic address: ronnie.shapira@sheba.health.gov.il. (62) Gustave Roussy Cancer Campus, INSERM U1015, Universite Paris-Saclay, 114 rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: sebastien.apcher@gustaveroussy.fr. (63) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: asafmadi@tauex.tau.ac.il. (64) University of Zurich, Faculty of Medicine, University Hospital of Zurich, Department of Dermatology, Schlieren 8952, Switzerland. Electronic address: mitchell.levesque@usz.ch. (65) Laboratory of Cancer Stemness, GIGA Institute, University of Lige, Lige, Belgium. Electronic address: francesca.rapino@uliege.be. (66) Department of Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yaroncarmi@gmail.com. (67) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA. Electronic address: ssparikh@mgh.harvard.edu. (68) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address: yardena.samuels@weizmann.ac.il. (69) Department of Human Genetics and Biochemistry, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@tauex.tau.ac.il.

Citation: Cell 2025 Dec 15 Epub12/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41401806

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Erythropoietin receptor on cDC1s dictates immune tolerance Featured  

(1) Zhang X (2) McGinnis CS (3) Yu G (4) Chen S (5) Zheng P (6) SchŸrch CM (7) Hiam-Galvez KJ (8) Reticker-Flynn NE (9) Guo W (10) Yao W (11) Qiu J (12) Muselman A (13) Linde IL (14) Hickey JW (15) Yan H (16) Tran VM (17) Qiu W (18) Brichart-Vernos D (19) Hirai T (20) Yu B (21) An X (22) Xiao Y (23) Paidassi H (24) Scharschmidt TC (25) Angelo M (26) Sheppard D (27) Chi H (28) Satpathy AT (29) Way SS (30) Malissen B (31) Strober S (32) Engleman EG

Nature

Investigating the induction of immune tolerance, Zhang et al. found that expression of erythropoietin receptor (EPOR) on cDC1s was upregulated in tolerogenic models and induced efferocytosis-induced maturation of cD1s towards a late stage, marked by expression of CCR7 and Itgb8. EPO enhanced induction of Tregs, while KO of EPOR or downstream Itgb8 reduced the expansion of Tregs and instead upregulated MHC-I and -II antigen presentation and costimulation molecules, supporting the induction of precursor exhausted, tumor antigen-specific CD8+ and conventional CD4+ T cells that could mediate immune rejection of allografts or tumors.

(1) Zhang X (2) McGinnis CS (3) Yu G (4) Chen S (5) Zheng P (6) SchŸrch CM (7) Hiam-Galvez KJ (8) Reticker-Flynn NE (9) Guo W (10) Yao W (11) Qiu J (12) Muselman A (13) Linde IL (14) Hickey JW (15) Yan H (16) Tran VM (17) Qiu W (18) Brichart-Vernos D (19) Hirai T (20) Yu B (21) An X (22) Xiao Y (23) Paidassi H (24) Scharschmidt TC (25) Angelo M (26) Sheppard D (27) Chi H (28) Satpathy AT (29) Way SS (30) Malissen B (31) Strober S (32) Engleman EG

Nature

Investigating the induction of immune tolerance, Zhang et al. found that expression of erythropoietin receptor (EPOR) on cDC1s was upregulated in tolerogenic models and induced efferocytosis-induced maturation of cD1s towards a late stage, marked by expression of CCR7 and Itgb8. EPO enhanced induction of Tregs, while KO of EPOR or downstream Itgb8 reduced the expansion of Tregs and instead upregulated MHC-I and -II antigen presentation and costimulation molecules, supporting the induction of precursor exhausted, tumor antigen-specific CD8+ and conventional CD4+ T cells that could mediate immune rejection of allografts or tumors.

ABSTRACT: Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis(1) and cross-presenting abilities(2), resulting in antigen-specific T cell immunity(3) or tolerance(4-8). However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown. Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance(9,10), cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3(+) regulatory T (T(reg)) cells, resulting in allograft rejection. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation(7,11) of splenic cDC1s towards late-stage CCR7(+) cDC1s characterized by increased expression of the integrin _8 gene(12) (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3(+) T(reg) cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7(+) cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8(+) T cells(13) in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural T(reg) cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.

Author Info: (1) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. xiangyue@stanford.edu. (2) Department of Pathology, School of Medicine, Stanford Universit

Author Info: (1) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. xiangyue@stanford.edu. (2) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (3) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (4) Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA. (5) Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, School of Medicine, Stanford University, Palo Alto, CA, USA. (6) Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center TŸbingen, TŸbingen, Germany. Cluster of Excellence iFIT (EXC 2180), Image-Guided and Functionally Instructed Tumor Therapies, University of TŸbingen, TŸbingen, Germany. (7) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (8) Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Stanford University, Stanford, CA, USA. (9) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (10) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (11) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (12) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (13) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (14) Department of Biomedical Engineering, Duke University, Durham, NC, USA. (15) Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, School of Medicine, Stanford University, Palo Alto, CA, USA. (16) Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. (17) Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (18) CIRI, Centre International de Recherche en Infectiologie, UniversitŽ de Lyon, Inserm U1111, UniversitŽ Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France. (19) Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, School of Medicine, Stanford University, Palo Alto, CA, USA. (20) ImmunEdge, Redwood City, CA, USA. (21) Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA. (22) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. (23) CIRI, Centre International de Recherche en Infectiologie, UniversitŽ de Lyon, Inserm U1111, UniversitŽ Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France. (24) Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. (25) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. (26) Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (27) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (28) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (29) Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. (30) Centre d'Immunologie de Marseille-Luminy, Aix-Marseille UniversitŽ, INSERM, CNRS, Marseille, France. (31) Department of Medicine (Immunology and Rheumatology), School of Medicine, Stanford University, Palo Alto, CA, USA. (32) Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA. edgareng@stanford.edu. Stanford Cancer Institute, School of Medicine, Stanford University, Palo Alto, CA, USA. edgareng@stanford.edu.

Citation: Nature 2025 Dec 10 Epub12/10/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41372415

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IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity

Featured  

Yihan Zuo 1, David J Vohwinkel 1, Bowen Dong 2, James R McDowell 1, Brandon V Guzman 1, Tharuna Sri Manickavel Pandian 2, Saborni Chattopadhyay 2, A J R McGray 2, Scott H Olejniczak 2, Joyce Ohm 3, Jianmin Wang 4, Mark D Long 4, Eduardo Cortes Gomez 4, Terence J Purdon 1, Wei Luo 5, Hemn Mohammadpour 6, Christopher S Hackett 7, Leonid Cherkassky 8, Marco Davila 1, Scott I Abrams 9, Renier J Brentjens 10

Cancer Cell

Zuo et al. assessed the efficacy of IL-36γ-armored DLL3- and GD3-dual-targeting CAR T cells across various tumor models. ​Dual-targeting CAR-T were more efficacious than single-targeting CAR-T, and the addition of IL-36γ armoring further improved efficacy. The IL-36γ-armored CAR-T treatment, with or without prior lymphodepletion, resulted in reprogramming of neutrophils in the TME. Neutrophils obtained antigen-presenting functionality, leading to epitope spreading and the induction of endogenous antitumor T cell responses to non-CAR-targeted tumor antigens.

Yihan Zuo 1, David J Vohwinkel 1, Bowen Dong 2, James R McDowell 1, Brandon V Guzman 1, Tharuna Sri Manickavel Pandian 2, Saborni Chattopadhyay 2, A J R McGray 2, Scott H Olejniczak 2, Joyce Ohm 3, Jianmin Wang 4, Mark D Long 4, Eduardo Cortes Gomez 4, Terence J Purdon 1, Wei Luo 5, Hemn Mohammadpour 6, Christopher S Hackett 7, Leonid Cherkassky 8, Marco Davila 1, Scott I Abrams 9, Renier J Brentjens 10

Cancer Cell

Zuo et al. assessed the efficacy of IL-36γ-armored DLL3- and GD3-dual-targeting CAR T cells across various tumor models. ​Dual-targeting CAR-T were more efficacious than single-targeting CAR-T, and the addition of IL-36γ armoring further improved efficacy. The IL-36γ-armored CAR-T treatment, with or without prior lymphodepletion, resulted in reprogramming of neutrophils in the TME. Neutrophils obtained antigen-presenting functionality, leading to epitope spreading and the induction of endogenous antitumor T cell responses to non-CAR-targeted tumor antigens.

ABSTRACT: Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicate primary solid tumors and enable rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulate the TME and reprogram unique neutrophil subsets with tumoricidal ability and antigen-(cross) presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.

Author Info: 1- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 2- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 1426

Author Info: 1- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 2- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 3- Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 4- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 5- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 6- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. 7- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. 8- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA. 9- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: Scott.Abrams@RoswellPark.org. 10- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: renier.brentjens@roswellpark.org.

Citation: Cancer cell 2025 Dec 11

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/41386225/

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Drilling dendritic cell activation- Engineering interfacial mechano-biochemical cues for enhanced immunotherapy

Spotlight 

Yali Ming (1,2); Jinji Wei (1,2); Zhaoyi Zhai (1,2); Zifeng Meng (3); Xiaonan Huang (1,2); Yuning Hu (1); Qi Huang (3); Guanghui Ma (1,2); Yufei Xia (1,2,4).

Cell Biomaterials

Ming et al. generated oil-water emulsions stabilized by alum particles (ASPEs) to mechanically activate DCs. Increasing alum crystallinity increased ASPE interfacial stiffness, in turn increasing DC contact area, membrane tension, and internalization, leading to PIEZO1-induced calcium flux and MAPK activation, altogether improving DC activation. Admixed with Ag, ASPEs induced a stronger Th1 responses in C57 mice compared to standard alum, increasing with ASPE stiffness. A high-stiffness ASPE incorporating MPLA adjuvant also induced strong, Th1-biased immune responses and improved efficacy over MPLA alone when used to prepare a DC vaccine.

Contributed by Alex Najibi

Yali Ming (1,2); Jinji Wei (1,2); Zhaoyi Zhai (1,2); Zifeng Meng (3); Xiaonan Huang (1,2); Yuning Hu (1); Qi Huang (3); Guanghui Ma (1,2); Yufei Xia (1,2,4).

Cell Biomaterials

Ming et al. generated oil-water emulsions stabilized by alum particles (ASPEs) to mechanically activate DCs. Increasing alum crystallinity increased ASPE interfacial stiffness, in turn increasing DC contact area, membrane tension, and internalization, leading to PIEZO1-induced calcium flux and MAPK activation, altogether improving DC activation. Admixed with Ag, ASPEs induced a stronger Th1 responses in C57 mice compared to standard alum, increasing with ASPE stiffness. A high-stiffness ASPE incorporating MPLA adjuvant also induced strong, Th1-biased immune responses and improved efficacy over MPLA alone when used to prepare a DC vaccine.

Contributed by Alex Najibi

ABSTRACT: A key challenge in immunotherapy is enhancing immune responses without introducing new molecular entities that trigger regulatory hurdles. While the size, shape, and composition of approved adjuvants have been optimized, their mechanical properties remain underexplored. Here, we repurpose approved aluminum-based adjuvants (alum) by engineering alum-stabilized Pickering emulsions (ASPEs) to synergize mechanical (PIEZO1) and biochemical (TLR4) cues. ASPEs, featuring interfacial alum with optimal rigidity, were heralded to promote an enlarged contact area with dendritic cells (DCs) during endocytosis, transmitting localized stress that activates PIEZO1-mediated calcium/mitogen-activated protein kinase (MAPK) signaling. This enhances antigen cross-presentation and Th1 immunity. Co-delivering a TLR4 agonist (monophosphoryl lipid A [MPLA]) further boosted immunogenicity in a varicella-zoster virus vaccine among aged mice, outperforming alum+MPLA (AS04). In antigen-pulsed DC therapy combined with PD-1 blockade, ASPE-M-treated DCs achieved a 2.11-fold greater tumor suppression compared with tumor lysate-M-based clinical approaches. These findings demonstrate how tuning the interfacial mechanics of approved materials can unlock mechano-immunotherapy with translational potential.

Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China (2) University of

Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China (2) University of Chinese Academy of Sciences, Beijing 100049, P.R. China (3) Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, P.R. China (4) Lead contact

Citation: Cell Biomaterial Dec 10, 2025

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Predicability of PD-L1 expression in cancer cells based solely on H&E-stained sections

(1) Faa G (2) Fraschini M (3) Ziranu P (4) Pretta A (5) Porcu G (6) Saba L (7) Scartozzi M (8) Shokun N (9) Rugge M

Journal of pathology informatics | Free PMC Article

(1) Faa G (2) Fraschini M (3) Ziranu P (4) Pretta A (5) Porcu G (6) Saba L (7) Scartozzi M (8) Shokun N (9) Rugge M

Journal of pathology informatics | Free PMC Article

PD-L1 expression is an important biomarker for selecting patients who are eligible for immune checkpoint inhibitor (ICI) therapy. However, evaluating PD-L1 through immunohistochemistry often faces significant interobserver variability and requires considerable time and resources. Recent advancements in artificial intelligence (AI) have transformed the field of pathology, leading to more standardized and reproducible methods for biomarker quantification. In this study, we examine the application of AI-driven models, particularly deep learning algorithms, to predict PD-L1 expression directly from hematoxylin and eosin-stained histological slides. Several AI-based approaches have been studied, demonstrating high accuracy in estimating PD-L1 expression and predicting responses to ICIs across various cancer types. AI-driven assessments of PD-L1 have been shown to reduce the subjectivity associated with manual scoring methods, such as the Tumor Proportion Score and the Combined Positive Score. Moreover, integrating AI with multimodal data, including genomics, radiomics, and real-world clinical data, can further enhance predictive accuracy and improve patient stratification for immunotherapy. Finally, AI-driven computational pathology offers a transformative approach to biomarker evaluation, providing a faster, more objective, and cost-effective alternative to traditional methods, with significant implications for personalized oncology and precision medicine. Despite these promising results, several challenges remain to be addressed, such as the need for large-scale validation, standardization of AI models, and regulatory approvals for clinical implementation. Tackling these issues will be crucial for incorporating AI-based PD-L1 assessments into routine pathology workflows.

Author Info: (1) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. Department of Biology, College of Science and Technology, Temple Un

Author Info: (1) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA. (2) Department of Electrical and Electronic Engineering, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (3) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (4) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (5) Department of Pathology, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy. (6) Department of Medical Sciences and Public Health, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (7) Medical Oncology Unit, University Hospital of Cagliari, Universitˆ degli Studi di Cagliari, 09123 Cagliari, Italy. (8) National Cancer Institute, Kyiv, Ukraine. Associazione "Angela Serra" per la ricerca sul cancro, Modena, Italy. (9) Department of Medicine - DIMED; General Anatomic Pathology and Cytopathology Unit, Universitˆ degli Studi di Padova, 35121 Padova, Italy.

Citation: J Pathol Inform 2025 Nov 19:100524 Epub10/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41340634

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