ACIR Journal Articles

A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes

(1) Srivastava N (2) Vomund AN (3) Yu R (4) Peterson OJ (5) Yang Y (6) Turicek DP (7) Abousaway O (8) Li T (9) Kain L (10) Stone P (11) Ansar A (12) Clement CC (13) Sharma S (14) Melhem R (15) Zhang B (16) Liu C (17) Joglekar AV (18) Hu H (19) Hsieh CS (20) Campisi L (21) Santambrogio L (22) Teyton L (23) Unanue ER (24) Arbelaez AM (25) Lichti CF (26) Wan X

Nature immunology

The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys_Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4(+) T cells that expand at diabetes onset. These neoepitope-specific CD4(+) T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.

Author Info: (1) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Hum

Author Info: (1) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (2) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (3) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (4) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (7) Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA. (8) Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA. (9) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (10) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (11) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (12) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (13) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (14) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. (15) Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA. (16) Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA. (17) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (18) Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. (19) Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA. (20) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. (21) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (23) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (24) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (25) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. clichti@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. clichti@wustl.edu. (26) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. wanx@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. wanx@wustl.edu.

Citation: Nat Immunol 2025 Nov 28 Epub11/28/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41315082

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial

(1) Baretti M (2) Kirk AM (3) Ladle BH (4) Kamdar Z (5) Bendinelli KJ (6) Ho WJ (7) Adhikari S (8) Clark NA (9) Sundararaman B (10) Wang H (11) Kung HC (12) Hernandez J (13) Qi H (14) Shin SM (15) Hernandez A (16) Nakazawa M (17) Schattgen SA (18) Crawford JC (19) Furth M (20) Anders RA (21) Thoburn C (22) Zaidi N (23) Huff AL (24) Nauroth J (25) Jaffee E (26) Pogorelyy MV (27) Thomas PG (28) Yarchoan M

Nature medicine

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting children and young adults that is driven by a chimeric protein, DNAJ-PKAc. The development of molecular inhibitors of DNAJ-PKAc has been hampered by unacceptable on-target toxicity, but the chimera results in a tumor-specific antigen (neoantigen) that may be targeted immunologically. Here we conducted a phase 1 clinical trial of a therapeutic peptide vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC, who had not previously received immune checkpoint therapy. The primary objectives were safety and T cell responses after week 10 (priming phase). Of the 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. The median age was 24_years (range 12-47_years). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from which we identified multiple class-II-restricted T cell receptors with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in T cell receptor repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or human leukocyte antigen loss. Our findings demonstrate the potential for therapeutic vaccines targeting 'undruggable' oncogenic drivers and suggest a rubric for evaluating effective anti-neoantigen immunity. ClinicalTrials.gov identifier: NCT04248569 .

Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Host-Microbe Interactions, St. Jude Childr

Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (8) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (9) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (10) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (14) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (17) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (18) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (19) Fibrolamellar Cancer Foundation, Greenwich, CT, USA. (20) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (22) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (23) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (24) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (26) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. (27) Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA. paul.thomas@stjude.org. (28) The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.

Citation: Nat Med 2025 Nov 24 Epub11/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41286513

Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial

(1) Iinuma T (2) Kurokawa T (3) Aoki T (4) Onodera A (5) Fukazawa T (6) Yamada D (7) Kitahara G (8) Okoshi M (9) Yamaguchi M (10) Okura H (11) Sasaki S (12) Sasako Y (13) Kira S (14) Sharif J (15) Tsuchiyama Y (16) Kobayashi M (17) Kobayashi N (18) Horikoshi T (19) Inaba Y (20) Hanaoka H (21) Okamoto Y (22) Hanazawa T (23) Koseki H (24) Motohashi S

Nature communications - Open Access

Invariant Natural killer T (iNKT) cells exhibit cytotoxic activity and immunomodulatory functions and have gained interest in cancer immunotherapy. We conducted a phase 1, first-in human clinical trial to evaluate the safety and efficacy of clinical-grade allogeneic iNKT cells generated from induced pluripotent stem cells (iPSC-iNKT cells) in patients with recurrent head and neck cancer (jRCT2033200116). The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were to assess safety and efficacy, as well as to evaluate immunological dynamics. iPSC-iNKT cells were administered intra-arterially to 10 patients. One subject developed grade 3 skin rash at the second dose, identified as DLT. No other severe adverse events were observed in any patients. Tumor progression was suppressed in two patients, in whom clonal expansion of memory- and effector-phenotype CD8(+) T cells was observed, along with activation of the IFN-_ signaling pathway. Here, we show that iPSC-iNKT cells are safe and possess therapeutic potential as an immunotherapy for solid tumors.

Author Info: (1) Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. (2) Department of Otorhinolaryngology, Head and Neck Surg

Author Info: (1) Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. (2) Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. Clinical Research Center, Chiba University Hospital, Chiba, Japan. (3) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (4) Research Institute of Disaster Medicine, Chiba University, Chiba, Japan. Institute for Advanced Academic Research, Chiba University, Chiba, Japan. (5) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (6) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (7) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (8) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (9) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (10) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (11) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (12) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (13) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (14) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (15) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. (16) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. (17) Center for Advanced Medicine, Chiba University Hospital, Chiba, Japan. (18) Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. (19) Clinical Research Center, Chiba University Hospital, Chiba, Japan. (20) Clinical Research Center, Chiba University Hospital, Chiba, Japan. (21) Chiba Rosai Hospital, Chiba, Japan. (22) Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. (23) Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Science, Kanagawa, Japan. haruhiko.koseki@riken.jp. Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan. haruhiko.koseki@riken.jp. (24) Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. motohashi@faculty.chiba-u.jp.

Citation: Nat Commun 2025 Nov 26 Epub11/26/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41298491

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells

(1) Luo Y (2) Hu T (3) Yao C (4) Wu T

Cancer immunology research - Open Access | Free PMC Article

(1) Luo Y (2) Hu T (3) Yao C (4) Wu T

Cancer immunology research - Open Access | Free PMC Article

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell-fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and T-cell receptor (TCR) profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T-cell activation and exhaustion compared to those recognizing other tumor antigens. In the tumor-draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared to clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph-node residence predicted a poorer response to immune checkpoint inhibitors by cancer patients. In conclusion, we have identified a transcriptional program that controls the cell-fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.

Author Info: (1) The University of Texas Southwestern Medical Center, Dallas, Texas, United States. (2) The University of Texas Southwestern Medical Center, Dallas, Texas, United States. (3) Th

Author Info: (1) The University of Texas Southwestern Medical Center, Dallas, Texas, United States. (2) The University of Texas Southwestern Medical Center, Dallas, Texas, United States. (3) The University of Texas Southwestern Medical Center, Dallas, Texas, United States. (4) The University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Citation: Cancer Immunol Res 2025 Oct 13 Epub10/13/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41081433

MHC-II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune-checkpoint inhibitors in cold tumors

(1) Song X (2) Lu C (3) Shi T (4) Wang H (5) Liu W (6) Luo Y (7) Zhou X (8) Wang Y (9) Ren S (10) Yu L (11) Liu B (12) Li Y (13) Wei J

Med

Song, Lu, and Shi et al. demonstrated that an MHC-II restricted neoantigen vaccine (M44) increased inflammatory signaling within the TME, enhanced CD4⁺ and CD8⁺ T cell infiltration, and reduced tumor growth in B16 tumors, while showing signs of T cell exhaustion. Vaccination increased the inferred interaction between TIGIT on T cells and its ligand PVR on myeloid cells, impairing the function and proliferation of Th1 and effector and memory CD8⁺ T cells. M44 vaccine plus TIGIT antibody inhibited tumor growth, enhanced the helper and cytotoxic functions of antigen-specific CD4⁺ T cells, and increased effector and memory CD8⁺ T cells.

Contributed by Shishir Pant

(1) Song X (2) Lu C (3) Shi T (4) Wang H (5) Liu W (6) Luo Y (7) Zhou X (8) Wang Y (9) Ren S (10) Yu L (11) Liu B (12) Li Y (13) Wei J

Med

Background: Cold tumors, characterized by poor T cell infiltration and an immunosuppressive tumor microenvironment (TME), are generally resistant to immune-checkpoint inhibitors (ICIs). Although CD4+ T cells play a critical role in anti-tumor immunity, it remains unclear whether major histocompatibility complex (MHC)-II-restricted neoantigen vaccines can reprogram the immunosuppressive TME and overcome ICI resistance.

Methods: Using the B16F10 model, we evaluated the MHC-II-restricted vaccine efficacy, profiled immune responses via flow cytometry and single-cell RNA sequencing, and identified the potential combination therapy targets poliovirus receptor (PVR) via NicheNet analysis. The combined efficacy was then validated in vitro and in vivo.

Findings: MHC-II-restricted neoantigen vaccine promoted inflammatory signaling within the TME and enhanced infiltration of CD4+ and CD8+ T cells, along with increased interferon (IFN)-γ production and signs of T cell exhaustion, which provided a prerequisite for ICI response. NicheNet analysis revealed enrichment of the inhibitory immune-checkpoint axis PVR-T cell immunoglobulin and ITIM domain (TIGIT) following vaccination. The combination of the vaccines and TIGIT blockade exhibited synergistic anti-tumor efficacy. This combination enhanced cytokine production by antigen-specific T cells, promoted effector memory differentiation, and delayed exhaustion of CD8+ T cells.

Conclusions: MHC-II-restricted neoantigen vaccine remodels the immune inhibitory TME with insufficient T cell infiltration and synergizes with TIGIT blockade to suppress tumor growth, providing a promising combinatorial strategy for cold tumors.

Funding: Supported by the National Key Research and Development Program of China (2023YFC2506400), the National Natural Science Foundation (82373263), and the Fundamental Research Funds for the Central Universities (0214-14380506).

Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) MOE Key Laboratory of Model Animal fo

Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China. (3) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (4) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (5) MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China. (6) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (7) Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China. (8) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (9) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (10) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (11) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (12) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China; Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi 214101, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China. Electronic address: yanli@nju.edu.cn. (13) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China; Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: jiawei99@nju.edu.cn.

Citation: Med 2025 Nov 26 100936 Epub11/26/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41308654

CD40 agonist improves the therapeutic efficacy of irreversible electroporation ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and TRM cell responses

(1) Wu Z (2) Yang Z (3) Iftikhar T (4) Groot G (5) Leary SC (6) Baniak N (7) Ahmed S (8) Bosch M (9) Moser M (10) Zhang W (11) Jiang J (12) Xiang J

Cancer immunology, immunotherapy - Open Access | Free PMC Article

(1) Wu Z (2) Yang Z (3) Iftikhar T (4) Groot G (5) Leary SC (6) Baniak N (7) Ahmed S (8) Bosch M (9) Moser M (10) Zhang W (11) Jiang J (12) Xiang J

Cancer immunology, immunotherapy - Open Access | Free PMC Article

Background: Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival.

Methods: In this study, we developed a novel IRE + Combo treatment regimen that combines IRE-ablation with Combo-adjuvant [CpG, anti-PD-L1 antibody (PD-L1-Ab) and CD40-agonist] and investigated its anti-tumor immunity in a mouse BL6-10OVA (BLOVA) melanoma model.

Results: We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8+ T cell response (6.89%) when compared with IRE + CpG/PD-L1-Ab (2.67%) or IRE alone (0.21%) treatments, leading to eradication of subcutaneous BLOVA melanoma in 5/8 of BLOVA-bearing mice and simultaneous elimination of lung melanoma metastases. Addition of CD40-agonist to the IRE + Combo treatment regimen also induced a higher frequency (17.1%) of CD8+CD103+ conventional type-1 dendritic cells (cDC1s) with up-regulated expression of CD54, CD80, MHC II, Bcl-xL and 41BBL in tumor-drainage lymph nodes (TDLNs) relative to the control IRE + CpG/PD-L1-Ab (12.1%) and IRE alone (9.0%) treatment groups. We also show that CD40-agonist stimulated a higher frequency of CD103+TCF1+ tissue-resident memory T (TRM) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these TRM cells exhibited enhanced mitochondrial content and greater relative expression of the effector cytokines IFN-γ and TNF-α and the transcriptional regulators TRAF1, p38-MAPK and PGC-1α.

Conclusion: Taken together, this study establishes that the CD40-agonist greatly potentiates the efficacy of IRE-ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and CD103+TCF1+ TRM cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.

Author Info: (1) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (2) Saskatoon Cancer Cent

Author Info: (1) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (2) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. (3) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (4) Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada. (5) Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada. (6) Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada. (7) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (8) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. (9) Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada. (10) Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SK, Canada. (11) Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. jiangjunhong1969@suda.edu.cn. (12) Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. jim.xiang@usask.ca. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. jim.xiang@usask.ca.

Citation: Cancer Immunol Immunother 2025 Nov 18 74:378 Epub11/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41251836

EVOLVE platform, a trispecific T cell engager with integrated CD2 costimulation, for the treatment of solid and hematologic tumors

(1) Sergeeva OA (2) Jin G (3) Sarkar M (4) Zeiger J (5) Dhindwal S (6) Chin SS (7) Abulizi A (8) Lai Z (9) Brown C (10) DeMaria WG (11) Ryan D (12) An X (13) Karp HJ (14) Teran E (15) Yuan C (16) Klaskin D (17) Reeve TA (18) Yu GK (19) Tam EM (20) Kaech SM (21) Preyer M (22) Matis L (23) Fine JS (24) Martomo SA (25) Myers JS

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

Sergeeva and Jin et al. developed the EVOLVE trispecific T cell engager (TCE) platform, comprising a tumor antigen-targeting domain, an affinity-attenuated CD3 agonist (optimized to increase T cell viability and effector function), and an LFA-3 extracellular domain fragment (to induce CD2 costimulation) in an IgG1 format, with Fc chain effector-inactivating mutations. EVOLVE TCEs exhibited greater tumor-killing potency than CD3 affinity-matched bispecifics in vitro, and induced greater, more durable antitumor activity and lower tumor antigen-dependent cytokine release than control (higher and lower affinity) CD3 TCEs in mouse xenograft models.

Contributed by Paula Hochman

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

ABSTRACT: Ten CD3 T cell engagers (TCEs) have received regulatory approval for the treatment of hematologic and solid tumors. However, limited costimulatory signaling essential for sustained T cell effector activity may limit CD3 TCE clinical efficacy and response duration. The CD2 receptor is an attractive costimulation target owing to its association with T cell receptor signaling and favorable expression profile. We show that CD2 costimulation is superior in maintaining T cell viability and effector function relative to other pathways in in vitro chronic stimulation assays. The extracellular domain of CD58, the predominant CD2 ligand, is functional as an antibody fusion, improving bispecific potency. We observe that higher CD3 affinity molecules have the potential for superagonism in the context of an integrated CD2 agonist. Evaluation of TCEs with integrated CD2 costimulation and attenuated CD3 binding identified optimal CD3 affinity agonists that avoid target-independent T cell activation and demonstrated an increased therapeutic index relative to nonattenuated CD3 agonists. This platform shows increased tumor-killing efficacy as compared to CD3 affinity-matched bispecifics for known tumor targets such as HER2, CD20, B7-H4, and UL16-binding protein 2 (ULBP2). We demonstrate that ULBP2-targeted trispecifics with integrated CD2 costimulation and optimized CD3 affinity are superior to higher-affinity CD3 molecules in in vivo mouse efficacy studies. This integrated CD2 costimulation platform, which we termed EVOLVE, represents a next-generation TCE platform to increase T cell effector function in the tumor microenvironment and has the potential to address unmet patient needs by improving the depth and durability of clinical antitumor T cell responses.

Author Info: (1) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (2) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (3) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (4) Evolv

Author Info: (1) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (2) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (3) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (4) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (5) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (6) EvolveImmune Therapeutics, Inc., Branford, CT 06405. Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591. (7) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (8) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (9) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (10) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (11) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (12) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (13) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (14) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (15) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (16) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (17) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (18) Independent Consultant, Kensington, CA 94708. (19) EvolveImmune Therapeutics, Inc., Branford, CT 06405. Antibody Technology Fred Hutchinson Cancer Center, Seattle, WA 98109. (20) NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037. (21) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (22) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (23) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (24) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (25) EvolveImmune Therapeutics, Inc., Branford, CT 06405.

Citation: Proc Natl Acad Sci U S A 2025 Nov 25 122:e2510829122 Epub11/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41252152

IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy

(1) Castelli S (2) Wilson WV (3) Uslu U (4) Finck AV (5) Rommel PC (6) Assenmacher CA (7) Atoche SJ (8) Siurala M (9) Aznar MA (10) Young RM (11) June CH

Immunity

Castelli et al. engineered CAR T cells with an authentic IL-9 receptor, which was tested in solid tumor models in combination with local IL-9 treatment. Treatment resulted in reduced tumor growth and improved survival. In human model systems, peripheral CAR–IL-9R T cells expanded, persisted, and had increased cytokine production, and resulted in higher tumoral infiltration. IL-9 signaling in CAR T cells resulted in a movement away from terminal T cell states, and toward less differentiated phenotypes and more proliferative effector states.

(1) Castelli S (2) Wilson WV (3) Uslu U (4) Finck AV (5) Rommel PC (6) Assenmacher CA (7) Atoche SJ (8) Siurala M (9) Aznar MA (10) Young RM (11) June CH

Immunity

ABSTRACT: The success of chimeric antigen receptor (CAR) T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment. We demonstrate that endowing CAR T cells with ectopic interleukin (IL)-9 signaling by co-expressing an IL-9 receptor rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at substantially lower doses than conventional products. Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8(+) T cell memory and effector states and promoting a CD4(+) cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 may contribute to the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.

Author Info: (1) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parke

Author Info: (1) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (5) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ryoung@upenn.edu. (11) Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: cjune@upenn.edu.

Citation: Immunity 2025 Nov 21 Epub11/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41274291

Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell-engineered mesothelin-redirected CAR-NKT cells

(1) Li YR (2) Shen X (3) Zhu E (4) Li Z (5) Huang J (6) Le T (7) Tran C (8) Radu CG (9) Yang L

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

Li et al. generated CAR-NKT cells by transducing cord blood HSPCs with an anti-mesothelin CAR, the iNKT TCR, and sIL-15, prior to a 6-week NKT differentiation protocol with high purity and yield. Compared to CAR T cells, CAR-NKT had reduced HLA expression, displayed an activated and memory phenotype, and killed both mesothelin-positive (via CAR) and -negative (via NK receptor) pancreatic cell lines. CAR-NKT also exhibited superior tumor distribution and efficacy in orthotopic and metastatic pancreatic tumor models, effectively treated mixed-antigen tumors, and showed lower risk for GvHD and CRS than CAR T.

Contributed by Alex Najibi

(1) Li YR (2) Shen X (3) Zhu E (4) Li Z (5) Huang J (6) Le T (7) Tran C (8) Radu CG (9) Yang L

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

ABSTRACT: Pancreatic cancer (PC) remains one of the leading causes of cancer-related mortality worldwide. The majority of patients are diagnosed at advanced stages, with over 50% presenting with metastatic disease at the time of diagnosis. Although chimeric antigen receptor (CAR)-T cell therapy has shown promise in targeting PC, its clinical efficacy remains limited due to several critical challenges. These include tumor antigen heterogeneity, antigen loss or escape mechanisms, functional exhaustion of CAR-T cells within the tumor microenvironment, as well as inherent limitations of autologous approaches such as high manufacturing costs, prolonged production timelines, and restricted scalability. To address these challenges, we developed allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T ((Allo15)MCAR-NKT) cells through gene engineering of human hematopoietic stem and progenitor cells (HSPCs) using a clinically guided culture method. These (Allo15)MCAR-NKT cells exhibited robust and multifaceted antitumor activity against PC, driven by both CAR and NK receptor-mediated cytotoxic mechanisms. In orthotopic and metastatic human PC xenograft models, (Allo15)MCAR-NKT cells demonstrated superior tumor control, enhanced trafficking and infiltration into tumor sites, sustained effector and cytotoxic phenotypes, and reduced expression of exhaustion markers. Importantly, (Allo15)MCAR-NKT cells demonstrated a favorable safety profile, characterized by the absence of graft-versus-host disease and minimal cytokine release syndrome. Collectively, these findings validate (Allo15)MCAR-NKT cells as a promising next-generation, off-the-shelf immunotherapeutic approach for PC, with the potential to overcome critical challenges including tumor heterogeneity, immune evasion, and therapeutic resistance, especially in the context of metastatic disease.

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angele

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. (6) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095. Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095. (7) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095. Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095. (8) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095. Department of Bioengineering, University of California, Los Angeles, CA 90095. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095. Molecular Biology Institute, University of California, Los Angeles, CA 90095. Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, CA 90095. Goodman-Luskin Microbiome Center, University of California, Los Angeles, CA

Citation: Proc Natl Acad Sci U S A 2025 Nov 25 122:e2517786122 Epub11/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41269799

Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells

(1) Hor JL (2) Schrom EC (3) Wong-Rolle A (4) Vistain L (5) Shang W (6) Dong Q (7) Zhao C (8) Jin C (9) Germain RN

Nature

(1) Hor JL (2) Schrom EC (3) Wong-Rolle A (4) Vistain L (5) Shang W (6) Dong Q (7) Zhao C (8) Jin C (9) Germain RN

Nature

ABSTRACT: Stem-like progenitors are self-renewing cytotoxic T cells that expand as effector cells during successful checkpoint immunotherapy(1,2). Emerging evidence suggests that tumour-draining lymph nodes support the continuous generation of these stem-like cells that replenish tumour sites and are a key source of expanded effector populations(3-6), underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Here, using advanced three-dimensional multiplex immunofluorescence imaging, we identify antigen-presentation niches in tumour-draining lymph nodes that support the expansion, maintenance and affinity evolution of TCF-1(+)PD-1(+)SLAMF6(high) stem-like CD8(+) T cells. Contrary to the prevailing view that persistent T cell receptor (TCR) signalling drives terminal effector differentiation, prolonged antigen engagement days beyond initial priming sustains the proliferation and self-renewal of these stem-like T cells in vivo. The inhibitory PD-1 pathway has a central role in this process through fine-tuning the TCR signal input that enables the selective expansion of high-affinity TCR stem-like clones as a renewable source of effector cells. PD-1 blockade disrupts this tuning, leading to terminal differentiation or death of the most avid anti-tumour stem-like cells. Our results therefore reveal a relationship between TCR ligand affinity recognition, a key negative-feedback regulatory loop and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 blockade during cancer immunotherapy provides a short-term anti-tumour effect at the cost of diminishing efficacy due to progressive loss of these critical high-affinity precursors.

Author Info: (1) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. jyhliang.hor@nih.gov. (2) Lymphocyte Biology Section, Laboratory of Immune Syste

Author Info: (1) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. jyhliang.hor@nih.gov. (2) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (3) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. (4) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (5) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (6) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. (8) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. rgermain@niaid.nih.gov. Center for Advanced Tissue Imaging, NIAID/NCI, NIH, Bethesda, MD, USA. rgermain@niaid.nih.gov.

Citation: Nature 2025 Nov 26 Epub11/26/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41299179

A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes

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A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial

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Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial

Tags:

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells

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MHC-II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune-checkpoint inhibitors in cold tumors

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CD40 agonist improves the therapeutic efficacy of irreversible electroporation ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and TRM cell responses

Tags:

EVOLVE platform, a trispecific T cell engager with integrated CD2 costimulation, for the treatment of solid and hematologic tumors

Tags:

IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy

Tags:

Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell-engineered mesothelin-redirected CAR-NKT cells

Tags:

Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells

Tags:

A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes

Tags:

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial

Tags:

Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial

Tags:

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells

Tags:

MHC-II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune-checkpoint inhibitors in cold tumors

Tags:

CD40 agonist improves the therapeutic efficacy of irreversible electroporation ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and TRM cell responses

Tags:

EVOLVE platform, a trispecific T cell engager with integrated CD2 costimulation, for the treatment of solid and hematologic tumors

Tags:

IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy

Tags:

Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell-engineered mesothelin-redirected CAR-NKT cells

Tags:

Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells

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