Journal Articles

16-h fasting optimizes cancer immunotherapy in mice and humans

(1) Chen S (2) Hu T (3) Zhu K (4) Liu Y (5) Yang Y (6) Li X (7) He J (8) Cui W (9) Chi Z (10) Yu W (11) Chen D (12) Wang Z (13) Zhang J (14) Sun R (15) Yang D (16) Dai S (17) Yu Q (18) Wang Q (19) Xiao Q (20) Qian J (21) Ding K (22) Wang D

Cell metabolism

Chen et al. designed an overnight 16h fasting regimen that augmented ICB efficacy in mice and patients with colorectal cancer. Fasting reprogrammed tumor cell nutrient preferences, triggering a metabolic trade-off that enriched intratumoral isoleucine (Ile). Ile fueled the acetyl-CoA pool in CD8+ T cells, which coordinated the epigenetic landscape and membrane lipid dynamics required for CD8+ T cell effector functions. Fasting reduced exhausted T cell populations, increased TEMRA and TRM effector functions, augmented the clonal expansion and cytotoxic activity of CD8+ T cells, and enhanced anti-PD-1 efficacy in preclinical models and patients with CRC.

Contributed by Shishir Pant

(1) Chen S (2) Hu T (3) Zhu K (4) Liu Y (5) Yang Y (6) Li X (7) He J (8) Cui W (9) Chi Z (10) Yu W (11) Chen D (12) Wang Z (13) Zhang J (14) Sun R (15) Yang D (16) Dai S (17) Yu Q (18) Wang Q (19) Xiao Q (20) Qian J (21) Ding K (22) Wang D

Cell metabolism

Chen et al. designed an overnight 16h fasting regimen that augmented ICB efficacy in mice and patients with colorectal cancer. Fasting reprogrammed tumor cell nutrient preferences, triggering a metabolic trade-off that enriched intratumoral isoleucine (Ile). Ile fueled the acetyl-CoA pool in CD8+ T cells, which coordinated the epigenetic landscape and membrane lipid dynamics required for CD8+ T cell effector functions. Fasting reduced exhausted T cell populations, increased TEMRA and TRM effector functions, augmented the clonal expansion and cytotoxic activity of CD8+ T cells, and enhanced anti-PD-1 efficacy in preclinical models and patients with CRC.

Contributed by Shishir Pant

ABSTRACT: Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8(+) T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8(+) clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.

Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University

Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (2) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (3) Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. (4) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (5) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (6) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (7) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (8) Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (9) Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Yiwu 322000, P.R. China. (10) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (11) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (12) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (13) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (14) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (15) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (16) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (17) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (18) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (19) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (20) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (21) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310020, P.R. China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310009, P.R. China. Electronic address: dingkefeng@zju.edu.cn. (22) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China; Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: diwang@zju.edu.cn.

Citation: Cell Metab 2026 Feb 19 Epub02/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41720105

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Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes

(1) Lai J (2) Chan CW (3) Armitage JD (4) Audsley KM (5) Huang YK (6) Derrick EB (7) Carstensen LS (8) Scheffler CM (9) Jones ME (10) Sek K (11) Principe N (12) Kim JS (13) House IG (14) Chen AXY (15) Yap KM (16) Middelburg J (17) Munoz I (18) Nguyen D (19) Tong J (20) Hoang TX (21) Todd KL (22) Evrard M (23) Chee J (24) Mackay LK (25) Forrest ARR (26) Parish IA (27) Bosco A (28) Waithman J (29) Beavis PA (30) Darcy PK

Nature immunology

Lai, Chan, Armitage, et al. investigated whether Flt3L treatment could improve immune checkpoint blockade responses. Flt3L increased cDC1 and stem-like precursor exhausted T cells (Tpex) populations through enhanced priming in the draining lymph nodes. Combining Flt3L treatment with CTLA-4 blockade resulted in expansion of stem-like and tumor antigen-specific effector T cell populations in the tumor, resulting in improved outcomes in mouse models.

(1) Lai J (2) Chan CW (3) Armitage JD (4) Audsley KM (5) Huang YK (6) Derrick EB (7) Carstensen LS (8) Scheffler CM (9) Jones ME (10) Sek K (11) Principe N (12) Kim JS (13) House IG (14) Chen AXY (15) Yap KM (16) Middelburg J (17) Munoz I (18) Nguyen D (19) Tong J (20) Hoang TX (21) Todd KL (22) Evrard M (23) Chee J (24) Mackay LK (25) Forrest ARR (26) Parish IA (27) Bosco A (28) Waithman J (29) Beavis PA (30) Darcy PK

Nature immunology

Lai, Chan, Armitage, et al. investigated whether Flt3L treatment could improve immune checkpoint blockade responses. Flt3L increased cDC1 and stem-like precursor exhausted T cells (Tpex) populations through enhanced priming in the draining lymph nodes. Combining Flt3L treatment with CTLA-4 blockade resulted in expansion of stem-like and tumor antigen-specific effector T cell populations in the tumor, resulting in improved outcomes in mouse models.

ABSTRACT: Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Vi

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia. The Kids Research Institute Australia, The University of Western Australia, Perth, Western Australia, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (9) Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (11) Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (18) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (22) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. (23) Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia. (24) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia. (25) Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (27) Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA. Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ, USA. (28) School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia. jason.waithman@uwa.edu.au. (29) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. paul.beavis@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. paul.beavis@petermac.org. (30) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. phil.darcy@petermac.org. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. phil.darcy@petermac.org. Department of Immunology, Monash University, Clayton, Victoria, Australia. phil.darcy@petermac.org.

Citation: Nat Immunol 2026 Feb 10 Epub02/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41667622

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Ex vivo expansion of melanoma tumor infiltrating lymphocytes leads to a dominant exhausted T cell population with lack of memory markers

(1) Coppola G (2) Kerr S (3) Cha PC (4) Bersenev A (5) Olino K (6) Kluger HM (7) Sznol M (8) Weiss SA (9) Bosenberg MW (10) Kleinstein SH (11) Krause DS (12) Hurwitz ME (13) Katz SG

Cancer immunology research

Using scRNA- and scTCRseq profiling, Coppola and Kerr et al. showed that large changes were induced during ex vivo expansion of TIL samples from six patients with metastatic melanoma. Post-expansion TILs lacked naive or memory cells, and were primarily exhausted, exhibiting decreased expression of PD-1, 4-1BB, and CD27, and increased expression of TIM3, LAG3, CD30, and cytotoxicity- and APC-associated genes. Although terminally differentiated, the expanded TILs contained a large progenitor exhausted CD8+ T cell population and increased absolute numbers of CD39/CD69 double-negative "stem-like" T cells, previously implicated for TIL efficacy.

Contributed by Paula Hochman

(1) Coppola G (2) Kerr S (3) Cha PC (4) Bersenev A (5) Olino K (6) Kluger HM (7) Sznol M (8) Weiss SA (9) Bosenberg MW (10) Kleinstein SH (11) Krause DS (12) Hurwitz ME (13) Katz SG

Cancer immunology research

Using scRNA- and scTCRseq profiling, Coppola and Kerr et al. showed that large changes were induced during ex vivo expansion of TIL samples from six patients with metastatic melanoma. Post-expansion TILs lacked naive or memory cells, and were primarily exhausted, exhibiting decreased expression of PD-1, 4-1BB, and CD27, and increased expression of TIM3, LAG3, CD30, and cytotoxicity- and APC-associated genes. Although terminally differentiated, the expanded TILs contained a large progenitor exhausted CD8+ T cell population and increased absolute numbers of CD39/CD69 double-negative "stem-like" T cells, previously implicated for TIL efficacy.

Contributed by Paula Hochman

ABSTRACT: Tumor infiltrating lymphocytes (TILs) can be isolated from patient tumors, greatly expanded ex vivo, and returned to the patient for therapeutic effect. Recent clinical trials have highlighted the efficacy of TILs for a subset of patients and supported FDA approval for melanoma. How TILs evolve during the manufacturing process is still unknown and likely critical to improving the therapy for more patients. To characterize cell modification during TIL expansion, we performed single-cell RNA- and TCR-sequencing of TILs isolated from patient tumors and their paired ex vivo expanded cell products. We found large transcriptional differences between pre- and post-expansion TILs. Post-expansion TILs were predominantly exhausted and lacked nave or memory cell phenotypes, including a decreased percentage of CD39/CD69 double negative (DN) "stem-like" T cells. Co-activating receptors CD137 and CD27 decreased while CD30 increased, whereas among co-inhibitory receptors PD1 decreased while TIM3 and LAG3 showed the largest increases with expansion. Other gene families that showed large increases with ex vivo growth included cytotoxicity- and APC-associated genes. Individual clonotypes were distributed among multiple cell differentiation states, which exhibited high degrees of plasticity during expansion. Although ex vivo expanded TILs are predominantly terminally differentiated, exhausted and transcriptionally highly distinct from the initial TILs, there is also a large progenitor exhausted CD8 T cell (Tpex) population and DN numbers increase. Future work to amplify subpopulations of TILs with memory cell phenotypes, such as the DN cells, will likely further improve this therapy.

Author Info: (1) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (2) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (3) Yale University

Author Info: (1) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (2) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (3) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (4) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (5) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (6) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (7) Yale University School of Medicine New Haven, CT United States. (8) Rutgers Cancer Institute New Brunswick, NJ United States. (9) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (10) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (11) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (12) Yale University New Haven, CT United States. ROR: https://ror.org/03v76x132 (13) Yale University New Haven, Connecticut United States. ROR: https://ror.org/03v76x132

Citation: Cancer Immunol Res 2026 Feb 13 Epub02/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41686210

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Sensitive detection of cancer antigens enabled by user-defined peptide libraries

(1) Manakongtreecheep K (2) Ctortecka C (3) Correa-Medero LO (4) Zhu T (5) Lippincott I (6) Lawrence GM (7) Howard A (8) Hernandez GM (9) Forman C (10) Duggan EC (11) Wilbrink MA (12) Verzani EK (13) Afeyan AB (14) Li J (15) Nesvizhskii AI (16) Oliveira G (17) Keskin DB (18) Ott PA (19) Clauser KR (20) Bakalar M (21) Sarkizova S (22) Hacohen N (23) Carr SA (24) Abelin JG (25) Wu CJ

Nature biotechnology

To support more sensitive immunopeptidomics analyses, Manakongtreecheep and Ctortecka et al. developed Pepyrus to rapidly and scalably generate user-defined peptide libraries in E. coli that could provide chromatographic and spectral references. Papyrus-enabled data-independent acquisition (DIA) allowed sensitive and high-confidence detection of lower-affinity and less abundant clinically relevant HLA-bound peptides, including neoantigens in complex patient samples. Further, a spectral library encompassing HIF-inducible ERVs for a renal cell carcinoma sample was reused “off-the-shelf” to analyze a melanoma sample, and identified ERV-derived peptides.

Contributed by Ute Burkhardt

(1) Manakongtreecheep K (2) Ctortecka C (3) Correa-Medero LO (4) Zhu T (5) Lippincott I (6) Lawrence GM (7) Howard A (8) Hernandez GM (9) Forman C (10) Duggan EC (11) Wilbrink MA (12) Verzani EK (13) Afeyan AB (14) Li J (15) Nesvizhskii AI (16) Oliveira G (17) Keskin DB (18) Ott PA (19) Clauser KR (20) Bakalar M (21) Sarkizova S (22) Hacohen N (23) Carr SA (24) Abelin JG (25) Wu CJ

Nature biotechnology

To support more sensitive immunopeptidomics analyses, Manakongtreecheep and Ctortecka et al. developed Pepyrus to rapidly and scalably generate user-defined peptide libraries in E. coli that could provide chromatographic and spectral references. Papyrus-enabled data-independent acquisition (DIA) allowed sensitive and high-confidence detection of lower-affinity and less abundant clinically relevant HLA-bound peptides, including neoantigens in complex patient samples. Further, a spectral library encompassing HIF-inducible ERVs for a renal cell carcinoma sample was reused “off-the-shelf” to analyze a melanoma sample, and identified ERV-derived peptides.

Contributed by Ute Burkhardt

ABSTRACT: Human leukocyte antigen (HLA)-bound tumor peptides can be routinely isolated from cancer samples and identified using mass spectrometry (MS). However, MS approaches can be stochastic or rely on spectral libraries, which are not customarily available for individual-specific peptides, thus limiting the ability to discover novel peptides. Here, we introduce Pepyrus, which generates user-defined, individual-specific or disease-specific peptide libraries in Escherichia coli to improve the sensitivity and confidence of MS peptide identification, including lowly abundant neoantigens. Using Pepyrus-generated peptide libraries paired with an HLA-specific data-independent acquisition strategy, we recover >75% of the expected sequences per single injection for libraries of >10,000 peptides and identify 0.1_fmol of spiked-in peptides in a complex background. We apply Pepyrus to create personalized libraries, facilitating identification of clinically relevant HLA peptides, including several novel peptides from cell lines derived from persons with melanoma and renal cell carcinoma. Pepyrus enables identification of rare HLA-bound peptides and provides the ability to generate large training datasets to improve spectra, retention time and ion mobility prediction tools.

Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. (2) Broad Institute of MIT and H

Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. (2) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Dana Farber Cancer Institute, Boston, MA, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Dana Farber Cancer Institute, Boston, MA, USA. (10) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Harvard Medical School, Boston, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. (14) Dana Farber Cancer Institute, Boston, MA, USA. (15) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (16) Dana Farber Cancer Institute, Boston, MA, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA. Technical University of Denmark, Lyngby, Denmark. (18) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Dana Farber Cancer Institute, Boston, MA, USA. (19) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (20) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (21) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. nhacohen@broadinstitute.org. Harvard Medical School, Boston, MA, USA. nhacohen@broadinstitute.org. Massachusetts General Hospital, Krantz Family Center for Cancer Research, Boston, MA, USA. nhacohen@broadinstitute.org. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. scarr@broad.mit.edu. (24) Broad Institute of MIT and Harvard, Cambridge, MA, USA. jabelin@broadinstitute.org. Dana Farber Cancer Institute, Boston, MA, USA. jabelin@broadinstitute.org. (25) Broad Institute of MIT and Harvard, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Dana Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu.

Citation: Nat Biotechnol 2026 Feb 9 Epub02/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41663542

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Transcription factor Etv3 controls the tolerogenic function of dendritic cells

(1) Adams NM (2) Martinez-Krams D (3) Esteva E (4) Ra AC (5) Alexiou AI (6) Jin H (7) Yun TJ (8) Tellaoui RS (9) Mudianto T (10) Vollmer E (11) Novikova E (12) Tan Y (13) Huntley W (14) Krichevsky O (15) Dolgalev I (16) Izmirly P (17) Buyon JP (18) Moreira AL (19) Lund AW (20) Reizis B

Science

Adams et al. identified Etv3 as a dendritic cell-intrinsic regulator of immune tolerance. Etv3 is induced during DC maturation and expressed in tissue-derived migratory DCs (migDCs). Etv3 cooperated with NF-κB to promote homeostatic migDC maturation and CCR7-dependent migration. Etv3 deficiency impaired migDC migration and induced upregulation of costimulatory molecules (including OX40L), driving dysfunctional CD25low Treg expansion, spontaneous T cell activation, and multi-organ inflammation. Loss of Etv3 worsened TLR7-driven systemic lupus erythematosus (SLE)-like disease, consistent with observations in human SLE.

Contributed by Shishir Pant

(1) Adams NM (2) Martinez-Krams D (3) Esteva E (4) Ra AC (5) Alexiou AI (6) Jin H (7) Yun TJ (8) Tellaoui RS (9) Mudianto T (10) Vollmer E (11) Novikova E (12) Tan Y (13) Huntley W (14) Krichevsky O (15) Dolgalev I (16) Izmirly P (17) Buyon JP (18) Moreira AL (19) Lund AW (20) Reizis B

Science

Adams et al. identified Etv3 as a dendritic cell-intrinsic regulator of immune tolerance. Etv3 is induced during DC maturation and expressed in tissue-derived migratory DCs (migDCs). Etv3 cooperated with NF-κB to promote homeostatic migDC maturation and CCR7-dependent migration. Etv3 deficiency impaired migDC migration and induced upregulation of costimulatory molecules (including OX40L), driving dysfunctional CD25low Treg expansion, spontaneous T cell activation, and multi-organ inflammation. Loss of Etv3 worsened TLR7-driven systemic lupus erythematosus (SLE)-like disease, consistent with observations in human SLE.

Contributed by Shishir Pant

ABSTRACT: Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25(low) regulatory T (T(reg)) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the T(reg) cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.

Author Info: (1) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (2) Department of Pathology, New York University Grossman School of Medicine, New Y

Author Info: (1) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (2) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (3) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, USA. (4) Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, USA. (5) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (6) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (7) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (8) Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA. (9) Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, USA. (10) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (11) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (12) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (13) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (14) Department of Physics, Ben Gurion University of the Negev, Beer-Sheva, Israel. Ilse Katz Institute for Nanoscale Science and Technology, Ben Gurion University of the Negev, Beer-Sheva, Israel. (15) Cellular Analytics Laboratory, New York University Grossman School of Medicine, New York, NY, USA. Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (16) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (17) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA. (18) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. (19) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, USA. (20) Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA. Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.

Citation: Science 2026 Feb 12 391:eads1246 Epub02/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41678619

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SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer

(1) Li B (2) Zhong MC (3) Galindo CC (4) Dou J (5) Qian J (6) Tang Z (7) Davidson D (8) Veillette A

Nature

Genetic studies by Li et al. showed that SLAMF6 (also known as Ly108) functioned to repress T cell activation in mice and humans by triggering homotypic cis interactions at the T cell surface, suppressing TCR signaling through SHP-1 and limiting antitumor immunity, independent of SLAMF6 expression on tumor cells or APCs. SLAMF6 was expressed preferentially on Tpex cells, but not terminally exhausted Tex cells, and potent agonist mAbs that blocked T cell SLAMF6 cis binding boosted T cell activation and increased antitumor T cell responses, decreased numbers of Tex cells, and inhibited tumor growth in vivo, comparable to results obtained with SLAMF6 deficiency.

Contributed by Katherine Turner

(1) Li B (2) Zhong MC (3) Galindo CC (4) Dou J (5) Qian J (6) Tang Z (7) Davidson D (8) Veillette A

Nature

Genetic studies by Li et al. showed that SLAMF6 (also known as Ly108) functioned to repress T cell activation in mice and humans by triggering homotypic cis interactions at the T cell surface, suppressing TCR signaling through SHP-1 and limiting antitumor immunity, independent of SLAMF6 expression on tumor cells or APCs. SLAMF6 was expressed preferentially on Tpex cells, but not terminally exhausted Tex cells, and potent agonist mAbs that blocked T cell SLAMF6 cis binding boosted T cell activation and increased antitumor T cell responses, decreased numbers of Tex cells, and inhibited tumor growth in vivo, comparable to results obtained with SLAMF6 deficiency.

Contributed by Katherine Turner

ABSTRACT: Inhibitory receptors like PD-1 and CTLA-4 contribute to T cell dysfunction in cancer(1-3). Monoclonal antibodies (mAbs) blocking the interactions in trans of these receptors with their ligands on cancer cells or in the tumour microenvironment lead to clinical responses in some but not all types of cancer. Signalling lymphocytic activation molecule 6 (SLAMF6, also known as Ly108) is a homotypic receptor preferentially expressed on progenitor or stem-like exhausted T (T(pex)) cells, but not on terminally exhausted T (T(ex)) cells, as demonstrated in mouse models(4-9). In contrast to T(ex) cells, T(pex) cells retain the capacity for functional restoration after immune checkpoint blockade(10-12). The role of SLAMF6 in T cells remains ambiguous, as it has both activating and inhibitory effects, complicating its evaluation as a therapeutic target. Here we find that SLAMF6 was triggered in cis by homotypic interactions at the T cell surface. These interactions elicited inhibitory effects that suppressed activation of T cells and limited anti-tumour immunity, independently of SLAMF6 expression on tumour cells. mAbs against human SLAMF6 with a robust ability to disrupt the cis interactions strongly augmented T cell activation, reduced the proportions of exhausted T cells and inhibited tumour growth in vivo. Collectively, these findings show that SLAMF6 functions exclusively as a T cell inhibitory receptor, which is triggered by cis homotypic interactions. They also position SLAMF6 as a promising target for therapies aimed at enhancing anti-tumour immunity, regardless of SLAMF6 expression on tumour cells.

Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. Department of Medicine, University of MontrŽal, Montreal, Quebe

Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. Department of Medicine, University of MontrŽal, Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (2) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. (3) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (4) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. Department of Medicine, McGill University, Montreal, Quebec, Canada. (5) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China. (7) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. (8) Laboratory of Molecular Oncology, Institut de recherches cliniques de MontrŽal (IRCM), Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, University of MontrŽal, Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca. Department of Medicine, McGill University, Montreal, Quebec, Canada. andre.veillette@ircm.qc.ca.

Citation: Nature 2026 Feb 11 Epub02/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41673151

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Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

(1) Huff AL (2) Haldar SD (3) Gergis AA (4) Wang HH (5) Danilova L (6) Heumann T (7) Berg M (8) Wang Y (9) Andaloori L (10) Hernandez A (11) Longway G (12) Barrett B (13) Zhu Z (14) Davis-Marcisak E (15) Thoburn C (16) Leatherman J (17) Mitchell S (18) Lee JW (19) Shu DH (20) Konig MF (21) Mog BJ (22) Montagne J (23) Coyne EM (24) Bever K (25) Baretti M (26) Yarchoan M (27) Anders RA (28) Kagohara LT (29) Laheru D (30) Thomas AM (31) Durham J (32) Nauroth JM (33) Lu J (34) Wang H (35) Fertig EJ (36) Ho WJ (37) Azad NS (38) Jaffee EM (39) Zaidi N

Nature communications | Free PMC Article

Huff et al. investigated a pooled peptide vaccine covering six KRAS mutations, plus ipilimumab and nivolumab in resected PDAC. mKRAS-specific T cell responses emerged in 11/12 patients, and 4/12 remained disease-free at ~36 months. Of the six KRAS mutations, G12D was the least immunogenic, and disease recurred in all patients with this mutation. Restimulated T cells were primarily CD4+, particularly Th1-like Tcm, and expressed mKRAS-reactive TCRs, including monoreactive, polyreactive, and public clonotypes. TCR-transduced T cell lines were activated by tumor cell lines pulsed with their cognate peptide, but not by controls, indicating TCR specificity.

Contributed by Morgan Janes

(1) Huff AL (2) Haldar SD (3) Gergis AA (4) Wang HH (5) Danilova L (6) Heumann T (7) Berg M (8) Wang Y (9) Andaloori L (10) Hernandez A (11) Longway G (12) Barrett B (13) Zhu Z (14) Davis-Marcisak E (15) Thoburn C (16) Leatherman J (17) Mitchell S (18) Lee JW (19) Shu DH (20) Konig MF (21) Mog BJ (22) Montagne J (23) Coyne EM (24) Bever K (25) Baretti M (26) Yarchoan M (27) Anders RA (28) Kagohara LT (29) Laheru D (30) Thomas AM (31) Durham J (32) Nauroth JM (33) Lu J (34) Wang H (35) Fertig EJ (36) Ho WJ (37) Azad NS (38) Jaffee EM (39) Zaidi N

Nature communications | Free PMC Article

Huff et al. investigated a pooled peptide vaccine covering six KRAS mutations, plus ipilimumab and nivolumab in resected PDAC. mKRAS-specific T cell responses emerged in 11/12 patients, and 4/12 remained disease-free at ~36 months. Of the six KRAS mutations, G12D was the least immunogenic, and disease recurred in all patients with this mutation. Restimulated T cells were primarily CD4+, particularly Th1-like Tcm, and expressed mKRAS-reactive TCRs, including monoreactive, polyreactive, and public clonotypes. TCR-transduced T cell lines were activated by tumor cell lines pulsed with their cognate peptide, but not by controls, indicating TCR specificity.

Contributed by Morgan Janes

ABSTRACT: In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

Author Info: (1) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins

Author Info: (1) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (2) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (4) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (6) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (7) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (9) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (10) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (13) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (14) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (16) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (17) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19) Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (22) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (23) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (24) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (25) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (26) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (27) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (28) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (29) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (30) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (31) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (32) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (33) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (34) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (35) Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. (36) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (37) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (38) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. ejaffee@jhmi.edu. (39) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu.

Citation: Nat Commun 2026 Feb 10 17:1538 Epub02/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41667470

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Persistent T cell activation and cytotoxicity against glioblastoma following single oncolytic virus treatment in a clinical trial Featured  

(1) Meylan M (2) Tian Y (3) Wu L (4) Ling AL (5) Kovarsky D (6) Barlow GL (7) Nguyen LD (8) Pyrdol J (9) Marx S (10) Westphal L (11) Michel J (12) Gonzalez Castro LN (13) Dumont S (14) Santos A (15) Tirosh I (16) Suvˆ ML (17) Chiocca EA (18) Wucherpfennig KW

Cell

Following clinical evidence that a single oncolytic virus treatment was associated with immune activation signatures, Meylen, Tiian, Wu, Ling, et al. analyzed tumor samples and found that pre-existing TILs expanded upon treatment, resulting in deep and persistent T cell activation against tumor cells. While viral remnants were restricted to necrotic regions, granzyme B+ CD8+ T cells embedded deeply into tumors, showed persistent activation, and were located in close proximity to apoptotic tumor cells. These T cell observations further and that this correlated with longer-progression-free and overall survival.

(1) Meylan M (2) Tian Y (3) Wu L (4) Ling AL (5) Kovarsky D (6) Barlow GL (7) Nguyen LD (8) Pyrdol J (9) Marx S (10) Westphal L (11) Michel J (12) Gonzalez Castro LN (13) Dumont S (14) Santos A (15) Tirosh I (16) Suvˆ ML (17) Chiocca EA (18) Wucherpfennig KW

Cell

Following clinical evidence that a single oncolytic virus treatment was associated with immune activation signatures, Meylen, Tiian, Wu, Ling, et al. analyzed tumor samples and found that pre-existing TILs expanded upon treatment, resulting in deep and persistent T cell activation against tumor cells. While viral remnants were restricted to necrotic regions, granzyme B+ CD8+ T cells embedded deeply into tumors, showed persistent activation, and were located in close proximity to apoptotic tumor cells. These T cell observations further and that this correlated with longer-progression-free and overall survival.

ABSTRACT: A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3(+) tumor cells and granzyme B(+) T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.

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

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (4) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. (5) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; German Cancer Research Center (DKFZ), JRG Hematology and Immune Engineering, Heidelberg, Germany. (12) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (16) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: suva.mario@mgh.harvard.edu. (17) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. Electronic address: eachiocca@mgb.org. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: kai_wucherpfennig@dfci.harvard.edu.

Citation: Cell 2026 Feb 11 Epub02/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41679299

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TNF-⍺-mediated myeloid-instructed CD14+CD4+ T cells are associated with poor survival in lung adenocarcinoma

Spotlight 

(1) Marceaux C (2) Tarasova I (3) Batey D (4) Yokote K (5) Gayevskiy V (6) Jain R (7) Leiwe M (8) Choux L (9) Riley L (10) Ribera NT (11) Yang E (12) Hywood J (13) Christie M (14) Antippa P (15) Speed TP (16) Rogers KL (17) Phipson B (18) Asselin-Labat ML

Cell reports. Medicine

Marceaux et al. performed spatial multi-omics analysis across clinically annotated LUAD and LUSC cohorts of NSCLC, and stratified it into lymphoid-, myeloid-, and mixed-enriched subtypes, independent of driver mutations. CD14⁺CD4⁺ T cells were enriched in myeloid niches and absent in healthy lungs. CD4+ T cells acquired CD14 from HLA-DR⁺ myeloid cells via trogocytosis, forming an atypical myeloid-instructed phenotype. TNFα signaling was enriched in CD14+CD4+ T cell-high tumors. The addition of TNF⍺ enhanced trogocytosis and CD14+CD4+ T cells formation ex vivo. CD14+CD4+ T cells represent a distinct T cell population associated with poor prognosis in NSCLC.

Contributed by Shishir Pant

(1) Marceaux C (2) Tarasova I (3) Batey D (4) Yokote K (5) Gayevskiy V (6) Jain R (7) Leiwe M (8) Choux L (9) Riley L (10) Ribera NT (11) Yang E (12) Hywood J (13) Christie M (14) Antippa P (15) Speed TP (16) Rogers KL (17) Phipson B (18) Asselin-Labat ML

Cell reports. Medicine

Marceaux et al. performed spatial multi-omics analysis across clinically annotated LUAD and LUSC cohorts of NSCLC, and stratified it into lymphoid-, myeloid-, and mixed-enriched subtypes, independent of driver mutations. CD14⁺CD4⁺ T cells were enriched in myeloid niches and absent in healthy lungs. CD4+ T cells acquired CD14 from HLA-DR⁺ myeloid cells via trogocytosis, forming an atypical myeloid-instructed phenotype. TNFα signaling was enriched in CD14+CD4+ T cell-high tumors. The addition of TNF⍺ enhanced trogocytosis and CD14+CD4+ T cells formation ex vivo. CD14+CD4+ T cells represent a distinct T cell population associated with poor prognosis in NSCLC.

Contributed by Shishir Pant

ABSTRACT: The tumor microenvironment is composed of diverse immune populations that can either support anti-tumor immunity or promote tumor progression. Myeloid cells are major drivers of immunosuppression, yet therapies targeting them have shown limited success. To uncover mechanisms underlying myeloid-driven immune suppression, we performed spatial multi-omics analyses of non-small cell lung cancer (NSCLC). Independent of oncogenic driver status, tumors stratify into lymphoid-enriched, myeloid-enriched, and mixed immune-infiltrated subtypes. In tumor and adjacent non-malignant lungs, we identify myeloid-instructed CD14+CD4+ T cells. These cells arise through trogocytosis adopting an atypical phenotype. In lymphoid-enriched tumors, high infiltration of CD14+CD4+ T cells correlates with poor patient survival. Spatial transcriptomics reveal enrichment of tumor necrosis factor alpha (TNF-α) signaling in CD14+CD4+-T-cell-rich tumors. Functional assays demonstrate that TNF-⍺ enhanced trogocytosis, promoting the formation of CD14+CD4+ T cells. These findings uncover a TNF-⍺-mediated mechanism of immunosuppression in the TME and highlight aberrant myeloid-T cell interactions as contributors to NSCLC progression.

Author Info: (1) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, P

Author Info: (1) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. (2) Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (3) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (4) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (5) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (6) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. (7) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. (8) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (9) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (10) Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (11) Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (12) The Royal Melbourne Hospital, Parkville, VIC, Australia. (13) The Royal Melbourne Hospital, Parkville, VIC, Australia. (14) Department of Surgery, The University of Melbourne, Parkville, VIC, Australia; The Royal Melbourne Hospital, Parkville, VIC, Australia. (15) Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia. (16) Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. (17) Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. (18) Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Mebourne, Parkville, VIC, Australia. Electronic address: labat@wehi.edu.au.

Citation: Cell Rep Med 2026 Feb 9 102593 Epub02/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41666923

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Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells Spotlight 

(1) Cohen IJ (2) Bochi-Layec AC (3) Lemoine J (4) Jenks S (5) Bayat P (6) Kim KH (7) Zhao H (8) Ugwuanyi O (9) Stella F (10) Ghilardi G (11) Gabrielli G (12) McCuaig S (13) Iatrou A (14) Vlachonikola E (15) Karipidou M (16) Bouziani E (17) Espie D (18) Ramasubramanian R (19) Agathangelidis A (20) Bhosale A (21) Paruzzo L (22) Medico G (23) Kolar B (24) Bugrovsky R (25) Guruprasad P (26) Wang LP (27) Harris J (28) Arons E (29) Zhang Y (30) Pajarillo R (31) Kreiger PA (32) Day CP (33) Sahinalp SC (34) Wu CH (35) Santi A (36) Fulmer B (37) Cases M (38) Palmer MB (39) Porazzi P (40) Wherry EJ (41) Kreitman RJ (42) Tiacci E (43) Apostolidis SA (44) Behrens EM (45) Bhoj V (46) Sanz I (47) Inghirami G (48) Schuster SJ (49) Ghia P (50) Stamatopoulos K (51) Ruella M

Science translational medicine

Focused on key challenges of CD19 CAR T cell therapy, such as on-target/off-tumor healthy B cell depletion and antigen-negative escape and relapse, Cohen, Bochi-­Layec and Lemoine et al. developed CAR T cells targeting the BCR-carrying IGHV-34 (CART4-34), which is highly enriched in B cell cancers, SLE, and other autoimmune diseases. CART4-34 potently killed malignant B cells and pathogenic B cells in SLE ex vivo, while sparing normal IGHV-34-negative B cells. In preclinical models, CART4-­34 showed robust expansion and antitumor activity, comparable to CART19, but was associated with reduced antigen-negative escape following treatment.

Contributed by Katherine Turner

(1) Cohen IJ (2) Bochi-Layec AC (3) Lemoine J (4) Jenks S (5) Bayat P (6) Kim KH (7) Zhao H (8) Ugwuanyi O (9) Stella F (10) Ghilardi G (11) Gabrielli G (12) McCuaig S (13) Iatrou A (14) Vlachonikola E (15) Karipidou M (16) Bouziani E (17) Espie D (18) Ramasubramanian R (19) Agathangelidis A (20) Bhosale A (21) Paruzzo L (22) Medico G (23) Kolar B (24) Bugrovsky R (25) Guruprasad P (26) Wang LP (27) Harris J (28) Arons E (29) Zhang Y (30) Pajarillo R (31) Kreiger PA (32) Day CP (33) Sahinalp SC (34) Wu CH (35) Santi A (36) Fulmer B (37) Cases M (38) Palmer MB (39) Porazzi P (40) Wherry EJ (41) Kreitman RJ (42) Tiacci E (43) Apostolidis SA (44) Behrens EM (45) Bhoj V (46) Sanz I (47) Inghirami G (48) Schuster SJ (49) Ghia P (50) Stamatopoulos K (51) Ruella M

Science translational medicine

Focused on key challenges of CD19 CAR T cell therapy, such as on-target/off-tumor healthy B cell depletion and antigen-negative escape and relapse, Cohen, Bochi-­Layec and Lemoine et al. developed CAR T cells targeting the BCR-carrying IGHV-34 (CART4-34), which is highly enriched in B cell cancers, SLE, and other autoimmune diseases. CART4-34 potently killed malignant B cells and pathogenic B cells in SLE ex vivo, while sparing normal IGHV-34-negative B cells. In preclinical models, CART4-­34 showed robust expansion and antitumor activity, comparable to CART19, but was associated with reduced antigen-negative escape following treatment.

Contributed by Katherine Turner

ABSTRACT: Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34(+) serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34(+) malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34(+) BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34(+) HBL1 cell line-derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34(+) SLE B cells and deplete IGHV4-34(+) autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.

Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia

Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (12) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (13) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (14) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (15) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (16) Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (17) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. Division of Genetics and Biotechnology, Department of Biology, National and Kapodistrian University of Athens, Athens 15772, Greece. (20) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY 10065, USA. (23) LatchBio, San Francisco, CA 94107, USA. (24) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (26) Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (28) Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (30) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (31) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (32) Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (33) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (34) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (35) Institute of Hematology and Center for Hemato-Oncology Research, Department of Medicine and Surgery, University and Hospital of Perugia, Perugia 06129, Italy. (36) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (37) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (38) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (39) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (40) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (41) Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (42) Institute of Hematology and Center for Hemato-Oncology Research, Department of Medicine and Surgery, University and Hospital of Perugia, Perugia 06129, Italy. (43) Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (44) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (45) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine and Therapeutic Pathology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (46) Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. (47) Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY 10065, USA. (48) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA. (49) Medical School, Universitˆ Vita-Salute San Raffaele, Milan 20132, Italy. B cell Neoplasia Unit, Comprehensive Cancer Center, IRCCS Ospedale San Raffaele, Milan 20132, Italy. (50) Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece. (51) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Division of Hematology/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA.

Citation: Sci Transl Med 2026 Feb 4 18:eadr9382 Epub02/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41637528

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