Journal Articles

ANKRD11 deficiency reprograms CD8+ T cell differentiation to enhance immunity in chronic infection and cancer

(1) Xu W (2) Guo J (3) Cao X (4) Li L (5) Xiao P (6) Zhang X (7) Jin Q (8) Zhang F (9) Hou B (10) Li M (11) Zhou X

Nature immunology

Using novel Tg mouse models, Xu et al. identified a TCR specific for a clinically relevant epitope rarely expressed on CD8+ T cells in chronic HBV infection. Efficacy of the specific TCR+ CD8+ T cells in a murine chronic HBV infection model was restrained by the immunosuppressive liver environment. Genome-wide CRISPR-Cas9 KO screening identified the mediator of such T cell restraint as ankyrin repeat domain11 (Ankrd11), a chromatin regulator that acts to break AP-1 family gene transcription. Ankrd11 deficiency in T cells boosted T cell expansion and differentiation of TPEX and PD-1-TOX- tolerant cells into effectors of murine antiviral and antitumor responses.

Contributed by Paula Hochman

(1) Xu W (2) Guo J (3) Cao X (4) Li L (5) Xiao P (6) Zhang X (7) Jin Q (8) Zhang F (9) Hou B (10) Li M (11) Zhou X

Nature immunology

Using novel Tg mouse models, Xu et al. identified a TCR specific for a clinically relevant epitope rarely expressed on CD8+ T cells in chronic HBV infection. Efficacy of the specific TCR+ CD8+ T cells in a murine chronic HBV infection model was restrained by the immunosuppressive liver environment. Genome-wide CRISPR-Cas9 KO screening identified the mediator of such T cell restraint as ankyrin repeat domain11 (Ankrd11), a chromatin regulator that acts to break AP-1 family gene transcription. Ankrd11 deficiency in T cells boosted T cell expansion and differentiation of TPEX and PD-1-TOX- tolerant cells into effectors of murine antiviral and antitumor responses.

Contributed by Paula Hochman

ABSTRACT: CD8(+) T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8(+) T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8(+) T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1(-)TOX(-) tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.

Author Info: (1) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Acad

Author Info: (1) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (2) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. (3) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (4) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (5) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (6) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (7) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (8) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (9) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China. (10) Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China. wuhm2000@sina.com. HBV Infection, Clinical Cure and Immunology Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. wuhm2000@sina.com. Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China. wuhm2000@sina.com. (11) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. zhouxy@im.ac.cn. Medical School, University of Chinese Academy of Sciences, Beijing, China. zhouxy@im.ac.cn.

Citation: Nat Immunol 2026 Sep 11 Epub09/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42728401

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Antibodies against HLA-E-VL9 enhance NK cell and CD8+ T cell cytotoxicity against tumor cells and HIV-infected CD4+ T cells

(1) Hwang JK (2) Tuyishime M (3) Marston DJ (4) Yang H (5) Wrapp D (6) Li D (7) Brackenridge S (8) Frazier M (9) Levering NP (10) Scearce R (11) Rhodes B (12) Harris C (13) Quastel M (14) Kapingidza AB (15) Kliszczak AE (16) Gater J (17) Borrow P (18) Ferrari G (19) Gillespie GM (20) McMichael AJ (21) Haynes BF (22) Azoitei ML

Science translational medicine

Hwang et al. engineered high-affinity antibodies against HLA-E–VL9 using structure-based design and high-throughput library screening to block inhibitory NKG2A/CD94 interactions. HLA-E–VL9 mAbs enhanced direct NK cell killing and NK-mediated ADCC against HLA-E–VL9+ tumors in vitro and K562HLA-E–VL9 tumors in vivo. HIV-infected primary CD4+ T cells expressed HLA-E–VL9, and HLA-E–VL9 mAbs mediated NK cell ADCC that selectively eliminated activated or infected CD4+ T cells over resting CD4+ T cells. HLA-E–VL9 blockade also enhanced NKG2A+CD8+ T cell-mediated HIV-specific cytotoxicity.

Contributed by Shishir Pant

(1) Hwang JK (2) Tuyishime M (3) Marston DJ (4) Yang H (5) Wrapp D (6) Li D (7) Brackenridge S (8) Frazier M (9) Levering NP (10) Scearce R (11) Rhodes B (12) Harris C (13) Quastel M (14) Kapingidza AB (15) Kliszczak AE (16) Gater J (17) Borrow P (18) Ferrari G (19) Gillespie GM (20) McMichael AJ (21) Haynes BF (22) Azoitei ML

Science translational medicine

Hwang et al. engineered high-affinity antibodies against HLA-E–VL9 using structure-based design and high-throughput library screening to block inhibitory NKG2A/CD94 interactions. HLA-E–VL9 mAbs enhanced direct NK cell killing and NK-mediated ADCC against HLA-E–VL9+ tumors in vitro and K562HLA-E–VL9 tumors in vivo. HIV-infected primary CD4+ T cells expressed HLA-E–VL9, and HLA-E–VL9 mAbs mediated NK cell ADCC that selectively eliminated activated or infected CD4+ T cells over resting CD4+ T cells. HLA-E–VL9 blockade also enhanced NKG2A+CD8+ T cell-mediated HIV-specific cytotoxicity.

Contributed by Shishir Pant

ABSTRACT: A major natural killer (NK) cell and CD8(+) T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, human leukocyte antigen E (HLA-E) complexed with nine-amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high-throughput library screening to generate high-affinity antibodies that block NKG2A/CD94 interactions. These antibodies enabled direct NK and CD8(+) T cell cytotoxicity and mediated NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies enhanced human NK cell line NK-92 killing of HLA-E-VL9(+) human tumors in mice, demonstrating checkpoint inhibition activity in vivo. Moreover, HLA-E-VL9 was found to be expressed on primary human CD4(+) T cells infected with HIV in vitro, and its engagement by HLA-E-VL9 antibodies drove elimination of infected cells by NK cell-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94(+) CD8(+) T cells targeting an HIV Rev-derived epitope that complexes with HLA-E. Therefore, anti-HLA-E-VL9 antibodies represent a candidate therapeutic approach to eliminating pathogenic target cells by enhancing both NK cell and CD8(+) T cell function and by promoting ADCC.

Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department o

Author Info: (1) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (2) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (3) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (4) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (5) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (6) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (7) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (8) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (9) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (10) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (11) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (12) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA. (13) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (14) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. (15) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (16) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (17) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (18) Department of Surgery, Duke University School of Medicine, Durham, NC, USA. (19) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (20) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (21) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Medicine, Duke University School of Medicine, Durham, NC, USA. Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA. (22) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.

Citation: Sci Transl Med 2026 Sep 16 18:eaea3879 Epub09/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42748220

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Identification of broadly tumour-reactive γδ TCRs from multiple myeloma

(1) St Paul M (2) Hendrikse LD (3) Ying F (4) Snow BE (5) Luo P (6) Helke S (7) Smith LK (8) Hilal A (9) Abelman DD (10) Ramamurthy N (11) Nault H (12) Wei EN (13) Gold MJ (14) Tobin C (15) Lien SC (16) Liu Y (17) Zhou W (18) Zhang X (19) Nguyen D (20) Agbede O (21) Pedersen S (22) Eagles J (23) Saunders ME (24) Berger T (25) Wakeham A (26) Scott DS (27) Ly D (28) de Campos CB (29) Liang G (30) Zheng C (31) Wilson WV (32) Masih-Khan E (33) White D (34) McCurdy A (35) Louzada ML (36) Kotb R (37) Chu MP (38) Parkin S (39) Reece D (40) Gul E (41) Tiedemann R (42) Pugh TJ (43) Hirano N (44) Ohashi PS (45) Stewart AK (46) Trudel S (47) Mak TW

Nature

St. Paul and Hendrikse et al. used single-cell sequencing and developed a machine-learning algorithm (PreGame) to distinguish the enigmatic tumor-reactive γδ T cells (TRγδ T cells) from bystander cells and confirm their specificity. From MM patient bone marrow, PreGame identified TRγδ T cells that recognized broadly expressed tumor antigens in a TCR-dependent manner. Responsive patients treated with a BCMA-targeted ADC exhibited significant expansion of TRγδ T cells and of γδ TCRs in cfDNA, which correlated with favorable responses and served as an early response biomarker. A γδ TCR epitope in the ubiquitously expressed HLA-C protein was identified.

Contributed by Katherine Turner

(1) St Paul M (2) Hendrikse LD (3) Ying F (4) Snow BE (5) Luo P (6) Helke S (7) Smith LK (8) Hilal A (9) Abelman DD (10) Ramamurthy N (11) Nault H (12) Wei EN (13) Gold MJ (14) Tobin C (15) Lien SC (16) Liu Y (17) Zhou W (18) Zhang X (19) Nguyen D (20) Agbede O (21) Pedersen S (22) Eagles J (23) Saunders ME (24) Berger T (25) Wakeham A (26) Scott DS (27) Ly D (28) de Campos CB (29) Liang G (30) Zheng C (31) Wilson WV (32) Masih-Khan E (33) White D (34) McCurdy A (35) Louzada ML (36) Kotb R (37) Chu MP (38) Parkin S (39) Reece D (40) Gul E (41) Tiedemann R (42) Pugh TJ (43) Hirano N (44) Ohashi PS (45) Stewart AK (46) Trudel S (47) Mak TW

Nature

St. Paul and Hendrikse et al. used single-cell sequencing and developed a machine-learning algorithm (PreGame) to distinguish the enigmatic tumor-reactive γδ T cells (TRγδ T cells) from bystander cells and confirm their specificity. From MM patient bone marrow, PreGame identified TRγδ T cells that recognized broadly expressed tumor antigens in a TCR-dependent manner. Responsive patients treated with a BCMA-targeted ADC exhibited significant expansion of TRγδ T cells and of γδ TCRs in cfDNA, which correlated with favorable responses and served as an early response biomarker. A γδ TCR epitope in the ubiquitously expressed HLA-C protein was identified.

Contributed by Katherine Turner

ABSTRACT: γδ T cells are becoming increasingly appreciated for their antitumour capacity and role in mediating responses to immune checkpoint blockade1-3. Unlike classical αβ T cells, the degree to which γδ T cells rely on their T cell receptors (TCRs) to induce antitumour responses remains unclear. The challenge of distinguishing γδ T cells with tumour-reactive TCRs from bystander γδ T cells limits our understanding of tumour-reactive γδ T cell biology and the translation of their TCRs into immunotherapeutics. Here we present PreGame, a machine-learning algorithm capable of identifying tumour-reactive γδ T cells from single-cell CITE sequencing data. We use PreGame to identify tumour-reactive γδ T cells from patients with multiple myeloma or other solid cancers, and confirm the specificity of their TCRs to tumour cells. Clinically, we demonstrate that expansion of tumour-reactive γδ T cells is an early biomarker of response in patients with multiple myeloma receiving combination therapy with belantamab mafodotin. We also identify a γδ TCR epitope in the ubiquitously expressed HLA-C protein and a logic gate that enables tumour immunosurveillance. Thus, PreGame is a versatile tool that can accelerate our understanding of γδ T cell biology and facilitate the translation of γδ TCRs into universal therapeutics.

Author Info: (1) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. michael.stpaul@uhn.ca. (2) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. liam.hendrikse@uhn.ca. (3) Prin

Author Info: (1) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. michael.stpaul@uhn.ca. (2) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. liam.hendrikse@uhn.ca. (3) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (4) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (5) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Computer Science and Mathematics, Faculty of Computer Science and Technology, Algoma University, Brampton, Ontario, Canada. (6) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (7) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (8) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (9) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (10) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (11) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (12) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (13) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (14) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (15) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (16) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (17) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (18) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (19) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (20) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (21) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (22) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (23) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (24) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (25) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (26) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (27) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (28) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (29) Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. (30) Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. (31) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (32) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (33) Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada. (34) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (35) London Health Sciences Centre, London, Ontario, Canada. (36) CancerCare Manitoba, Winnipeg, Manitoba, Canada. (37) Cross Cancer Institute, Edmonton, Alberta, Canada. (38) Vancouver General Hospital, Vancouver, British Columbia, Canada. (39) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (40) Canadian Myeloma Research Group (CMRG), Vaughan, Ontario, Canada. (41) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (42) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. (43) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (44) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (45) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (46) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. suzanne.trudel@uhn.ca. (47) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. tak.mak@uhn.ca. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. tak.mak@uhn.ca. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. tak.mak@uhn.ca.

Citation: Nature 2026 Sep 16 Epub09/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42749802

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Characterization of circulating neoantigen-specific T cell responses and public T cell receptors shaping immune memory in Lynch syndrome carriers

(1) Duzagac F (2) Deng N (3) Wang J (4) Nagaraju S (5) Steinberger P (6) Reuben A (7) Sinha KM (8) Vilar E

Cell reports. Medicine

Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.

Contributed by Shishir Pant

(1) Duzagac F (2) Deng N (3) Wang J (4) Nagaraju S (5) Steinberger P (6) Reuben A (7) Sinha KM (8) Vilar E

Cell reports. Medicine

Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.

Contributed by Shishir Pant

ABSTRACT: Lynch syndrome (LS), a common inherited genetic condition predisposing to cancer, provides a unique model to study immune surveillance at the earliest stages of tumorigenesis. A hallmark of LS carcinogenesis is the generation of highly immunogenic neoantigens, yet the transcriptomic states of the T cells that recognize them remain poorly understood. Here, we characterize neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/T cell receptor (TCR) sequencing, and repertoire integration with existing large datasets. Recurrent neoantigens elicit strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against tumor organoids. Single-cell analysis reveals oligoclonal expansions spanning effector and memory states with enrichment for exhausted subsets among cancer survivors and retention of polyfunctional effectors in cancer-free carriers. Cross-cohort analysis identifies public TCR clonotypes in circulation that overlap with pre-cancer and tumor tissue repertoires. Together, these findings define the architecture of circulating neoantigen-specific immune memory in LS and highlight public TCRs as candidates for immune monitoring and immunoprevention.

Author Info: (1) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Clinical Cancer Prevention, The University of T

Author Info: (1) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Institute of Immunology, Medical University of Vienna, Vienna, Austria. (6) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: evilar@mdanderson.org.

Citation: Cell Rep Med 2026 Sep 18 103057 Epub09/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42759506

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Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models

(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

Cancer immunology research

Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

Contributed by Lauren Hitchings

(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

Cancer immunology research

Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

Contributed by Lauren Hitchings

ABSTRACT: To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.

Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4

Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (5) Hannover Medical School Hannover Germany. (6) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. (7) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (8) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (9) Glycotope GmbH Berlin Germany. (10) Medizinische Hochschule Hannover Hannover, Low Saxony Germany. ROR: https://ror.org/00f2yqf98 (11) Technische UniversitŠt Braunschweig Braunschweig Germany. ROR: https://ror.org/010nsgg66 (12) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (13) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (14) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (15) Leibniz Institute for Immunotherapy and Univ Regensberg Regensburg Germany. (16) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. ROR: https://ror.org/03pvr2g57 (17) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (18) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98

Citation: Cancer Immunol Res 2026 Sep 22 Epub09/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42770707

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CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer

(1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

Cell

Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

(1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

Cell

Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon _ (IFN-_), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-_ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2)

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (3) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (14) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (15) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (17) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (20) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (22) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (24) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (25) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (31) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (32) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (34) Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (36) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (37) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. (38) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (39) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

Citation: Cell 2026 Sep 23 Epub09/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42777708

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FasL-mediated death of activated intratumoral T cells drives secondary resistance to cancer immunotherapy Spotlight 

(1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

Cancer immunology research

Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

Contributed by Alex Najibi

(1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

Cancer immunology research

Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

Contributed by Alex Najibi

ABSTRACT: Cancer progression following an initial response to immunotherapy (secondary resistance; 2°R) is a major and poorly understood problem. We treated mice bearing B16 melanoma with a combination of a regulatory T cell (Treg) depleting, non-IL-2 blocking antibody (anti-CD25NIB) and an autologous cancer cell vaccine (GVAX). The regimen yielded initial tumor shrinkage followed by 2°R; lethal progression occurred in ~90% of partially responsive (PR) tumors by days 35-50. Cell lines derived from 2°R tumors retained treatment sensitivity upon re-implantation into naïve mice, suggesting resistance was related to a loss of immune control over time. Profiling PR and 2°R tumors by flow cytometry and single-cell RNA/TCR sequencing, we found that activated CD8⁺ T cells with tumor-reactive features declined in abundance, whereas non-activated T cells and Tregs increased. Activated CD8⁺ cells showed heightened TCR stimulation, clonal expansion, and expression of apoptotic signatures and death receptors, including Fas. Their loss was not explained by lymph node accumulation or differentiation to non-activated states. These findings were validated in a clinically relevant MC38 colon carcinoma model treated with anti-PD-L1 checkpoint blockade, confirming that depletion of activated, tumor-reactive clones is a shared mechanism of 2°R across therapeutic modalities. Fas ligand (FasL) blockade reversed this loss and prolonged survival. Longitudinal transcriptional and tissue staining data from human checkpoint blockade studies similarly indicated that activated T cells decline in abundance over time and at 2°R. These findings implicate death of activated T cells as a mechanism of 2°R and suggest Fas-FasL blockade may extend response durability.

Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer In

Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (4) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (5) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (6) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (7) University of Oxford Oxford United Kingdom. ROR: https://ror.org/052gg0110 (8) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (9) Roche (Switzerland) Schlieren Switzerland. ROR: https://ror.org/00by1q217 (10) University College London Cancer Institute, London United Kingdom. (11) University College London London United Kingdom. ROR: https://ror.org/02jx3x895

Citation: Cancer Immunol Res 2026 Sep 15 Epub09/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42743199

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Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma Spotlight 

(1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

Science translational medicine

Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

Contributed by Shishir Pant

(1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

Science translational medicine

Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Can

Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (5) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (9) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (13) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (14) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (16) Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (17) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (19) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (20) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (21) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (23) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (24) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Global Health, University of Washington School of Medicine, Seattle, WA 98195, USA. Benaroya Research Institute, Seattle, WA 98101, USA. (25) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (26) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (27) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (28) Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (29) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (30) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (31) Biomedical Data Science Center, Centre Hospitalier Universitaire Vaudois, 1010 Lausanne, Switzerland. University of Lausanne, 1015 Lausanne, Switzerland. School of Life Sciences, EPFL, 1015 Lausanne, Switzerland. (32) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (33) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Dermatology, University of Washington School of Medicine, Seattle, WA 98195, USA. (34) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.

Citation: Sci Transl Med 2026 Sep 9 18:eaea8773 Epub09/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42715345

Tags:

γδ T cells modulate anti-tumor immunity in small cell lung cancer

Spotlight 

(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD

Cancer cell

Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.

Contributed by Katherine Turner

(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD

Cancer cell

Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.

Contributed by Katherine Turner

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.

Author Info: (1) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The Univers

Author Info: (1) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: ng.ji@wehi.edu.au. (2) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (3) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (4) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (5) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (6) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Pathology, Faculty of Medicine and University of Hospital Cologne, University of Cologne, 50931 Cologne, Germany. (8) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (9) Clinical Translation, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Medicine, Adelaide University, Adelaide, SA 5000, Australia; Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden; Centre for Health Services Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (10) Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. (11) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (12) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 9RT, UK; Department of Medical Oncology, Guy's Hospital, London SE1 9RT, UK. (13) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (15) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (16) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (17) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (18) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (19) Department of Respiratory Medicine, Austin Health, Heidelberg, VIC 3084, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia. (20) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University Hospital of Cologne, 50931 Cologne, Germany. (21) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (22) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (23) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (24) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (25) Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Respiratory and Sleep Medicine, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia. (26) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sutherland.k@wehi.edu.au.

Citation: Cancer Cell 2026 Sep 18 Epub09/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42759517

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A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion Spotlight 

(1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

Nature

Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

Contributed by Shishir Pant

(1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

Nature

Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

Contributed by Shishir Pant

ABSTRACT: Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity(1-4). This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

Citation: Nature 2026 Sep 9 Epub09/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42717081

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