Journal Articles

ILT2 identifies an unexploited pool of intratumoral CD8+ bystander T cells with TCR-independent cytotoxicity in renal cell carcinoma

(1) Laboureur R (2) Dumont C (3) Koca D (4) Lugand L (5) Bossis M (6) Artru E (7) Jacquier A (8) Verine J (9) Bouhidel F (10) Djouadou M (11) Masson-Lecomte A (12) Russick J (13) Carosella ED (14) Desgrandchamps F (15) Guyon L (16) Tonnerre P (17) LeMaoult J (18) Rouas-Freiss N

Cancer immunology research

Analyzing primary ccRCC samples, Laboureur et al. identified a subset of CD8+ILT2+PD-1- TILs that were terminally differentiated and expressed high baseline levels of granzyme B, perforin, and NKG2D, but lacked tumor specificity and tissue residency markers. These “bystander” T cells, likely recruited from the periphery, exhibited CD3-driven activation and IFNγ production in response to viral antigens, as well as IL-15/NKG2D-driven, TCR-independent cytotoxicity. The innate-like cytotoxicity was inhibited by HLA-G (an ILT2 ligand expressed on tumor cells), suggestive of a checkpoint axis that could potentially be targeted for immunotherapy.

Contributed by Lauren Hitchings

(1) Laboureur R (2) Dumont C (3) Koca D (4) Lugand L (5) Bossis M (6) Artru E (7) Jacquier A (8) Verine J (9) Bouhidel F (10) Djouadou M (11) Masson-Lecomte A (12) Russick J (13) Carosella ED (14) Desgrandchamps F (15) Guyon L (16) Tonnerre P (17) LeMaoult J (18) Rouas-Freiss N

Cancer immunology research

Analyzing primary ccRCC samples, Laboureur et al. identified a subset of CD8+ILT2+PD-1- TILs that were terminally differentiated and expressed high baseline levels of granzyme B, perforin, and NKG2D, but lacked tumor specificity and tissue residency markers. These “bystander” T cells, likely recruited from the periphery, exhibited CD3-driven activation and IFNγ production in response to viral antigens, as well as IL-15/NKG2D-driven, TCR-independent cytotoxicity. The innate-like cytotoxicity was inhibited by HLA-G (an ILT2 ligand expressed on tumor cells), suggestive of a checkpoint axis that could potentially be targeted for immunotherapy.

Contributed by Lauren Hitchings

ABSTRACT: Immune checkpoint inhibitors (ICIs) have improved clear-cell renal cell carcinoma (ccRCC) therapy, yet many patients remain unresponsive. Alternative strategies are needed, and the HLA-G/ILT2 axis has emerged as a promising immunosuppressive pathway. Here, we deeply characterized CD8_ILT2_ tumor-infiltrating lymphocytes (TILs) as a distinct subset from CD8_PD1_ TILs in ccRCC, using high-dimensional spectral flow cytometry, single-cell transcriptomics, and TCR clonotype analysis. CD8_ILT2_ TILs were terminally differentiated, highly cytotoxic "bystander" cells, enriched for virus-specific TCRs. They phenotypically, transcriptionally and functionally mirrored their circulating counterparts, suggesting peripheral recruitment. In dynamic co-culture assays, they exhibited potent TCR-independent cytotoxicity, mediated by activating innate receptors, namely NKG2D. However, HLA-G inhibited this activity, underscoring the immune-evasive role of the HLA-G/ILT2 axis. Our study defines CD8_ILT2_ TILs as an untapped effector population with potential antitumor activity and a promising therapeutic target in ccRCC. These findings offer new insights into TIL functional diversity and pave the way for innovative immunotherapies beyond conventional ICIs.

Author Info: (1) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (2) H™pital Saint-Louis Paris France. ROR: https://ror.org/049am9t04 (3) CEA Grenoble Grenoble France. ROR:

Author Info: (1) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (2) H™pital Saint-Louis Paris France. ROR: https://ror.org/049am9t04 (3) CEA Grenoble Grenoble France. ROR: https://ror.org/02mg6n827 (4) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (5) Inserm Paris France. ROR: https://ror.org/02vjkv261 (6) Inserm Paris France. ROR: https://ror.org/02vjkv261 (7) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (8) APHP Paris France. (9) H™pital Saint-Louis, Assistance publique H™pitaux de Paris Paris France. (10) APHP Paris France. (11) Assistance Publique - H™pitaux de Paris Paris France. ROR: https://ror.org/00pg5jh14 (12) CEA Paris-Saclay - Etablissement de Fontenay-aux-roses Paris France. (13) Commissariat ˆ l'Energie Atomique et aux Energies Alternatives Paris France. (14) AP-HP, H™pital Saint-Louis Paris France. (15) Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA) Grenoble France. (16) Inserm Paris France. ROR: https://ror.org/02vjkv261 (17) CEA Fontenay-aux-Roses Paris France. ROR: https://ror.org/010j2gw05 (18) Atomic Energy and Alternative Energies Commission Paris France. ROR: https://ror.org/00jjx8s55

Citation: Cancer Immunol Res 2026 Jun 8 Epub06/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42258315

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Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma

(1) Di Pietro A (2) Au L (3) Crock P (4) Thio N (5) Pizzolla A (6) Nguyen TN (7) Macdonald S (8) Chalmers H (9) Zhu R (10) Airaghi A (11) Molden-Hauer T (12) Bacac M (13) Schwalie P (14) Schlenker R (15) Levesque MP (16) Mailer S (17) Barnes-Cullen K (18) Winch K (19) Chan J (20) Yeung GA (21) Spain L (22) Rao AD (23) Sandhu S (24) Gyorki DE (25) McArthur GA (26) Mackay LK (27) Neeson PJ

Nature communications

Pietro and Au et al. profiled melanoma lymph node metastases from untreated, ICB-resistant, and ICB-responsive patients using flow cytometry, mIHC, and single-cell transcriptomics to dissect tumor-resident (TR) T cell niches. ICB-responsive tumors were enriched for clonally expanded, cytotoxic CD8⁺ TR cells and cytotoxic/helper CD4⁺ TR cells within an immune-activated microenvironment, whereas ICB-resistant tumors displayed chronic IFNγ signaling, exhausted T cell states, and impaired clonal diversification. Spatial analyses identified CD8⁺ TRs, CD4⁺ TRs, and DC3s forming in situ immune triads as an essential feature of ICB responders.

Contributed by Shishir Pant

(1) Di Pietro A (2) Au L (3) Crock P (4) Thio N (5) Pizzolla A (6) Nguyen TN (7) Macdonald S (8) Chalmers H (9) Zhu R (10) Airaghi A (11) Molden-Hauer T (12) Bacac M (13) Schwalie P (14) Schlenker R (15) Levesque MP (16) Mailer S (17) Barnes-Cullen K (18) Winch K (19) Chan J (20) Yeung GA (21) Spain L (22) Rao AD (23) Sandhu S (24) Gyorki DE (25) McArthur GA (26) Mackay LK (27) Neeson PJ

Nature communications

Pietro and Au et al. profiled melanoma lymph node metastases from untreated, ICB-resistant, and ICB-responsive patients using flow cytometry, mIHC, and single-cell transcriptomics to dissect tumor-resident (TR) T cell niches. ICB-responsive tumors were enriched for clonally expanded, cytotoxic CD8⁺ TR cells and cytotoxic/helper CD4⁺ TR cells within an immune-activated microenvironment, whereas ICB-resistant tumors displayed chronic IFNγ signaling, exhausted T cell states, and impaired clonal diversification. Spatial analyses identified CD8⁺ TRs, CD4⁺ TRs, and DC3s forming in situ immune triads as an essential feature of ICB responders.

Contributed by Shishir Pant

ABSTRACT: Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8+ and CD4+ TR. CD8+ TR cells were clonally expanded, and both CD8+ and CD4+ TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.

Author Info: (1) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Austra

Author Info: (1) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (2) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (3) Bioinformatics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (4) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Bioinformatics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (5) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (12) Roche Innovation Center, Zurich, Switzerland. (13) Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. (14) Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. (15) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (16) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (17) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (18) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (19) Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (20) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (21) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (22) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (23) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (24) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (25) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Melanoma Research Victoria, Melbourne, VIC, Australia. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (26) Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. (27) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. paul.neeson@petermac.org. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. paul.neeson@petermac.org.

Citation: Nat Commun 2026 Jun 11 Epub06/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42277002

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An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function

(1) Min IM (2) Yang Y (3) Stefanova D (4) Vedvyas Y (5) Babu DS (6) Lee DH (7) Alcaina Y (8) Riascos MC (9) Puc J (10) Chen KJ (11) Gonzalez-Valdivieso J (12) Thaiparambil J (13) Bilal M (14) He B (15) Burnett AC (16) Zarnegar R (17) Fahey TJ (18) Jin MM

Cancer immunology research

Min et al. developed an ICAM1-specific 4-1BB fusion protein. Engagement of this chimeric costimulatory receptor (ICCR) enhanced tumor cell conjugation and force-dependent immune synapse stability, triggered NF-κB-signaling, and amplified TCR-driven functional activation of engineered T cells, particularly against targets with lower antigen density. In a patient-derived orthotropic xenograft model of aggressive, incurable thyroid cancer, autologous ICCR+ T cells showed selective expansion and prolongation of survival. ICCR+ T cells exhibited reduced TCR diversity, and upregulation of cytotoxicity, TCR signaling, costimulation, and exhaustion genes.

Contributed by Ute Burkhardt

(1) Min IM (2) Yang Y (3) Stefanova D (4) Vedvyas Y (5) Babu DS (6) Lee DH (7) Alcaina Y (8) Riascos MC (9) Puc J (10) Chen KJ (11) Gonzalez-Valdivieso J (12) Thaiparambil J (13) Bilal M (14) He B (15) Burnett AC (16) Zarnegar R (17) Fahey TJ (18) Jin MM

Cancer immunology research

Min et al. developed an ICAM1-specific 4-1BB fusion protein. Engagement of this chimeric costimulatory receptor (ICCR) enhanced tumor cell conjugation and force-dependent immune synapse stability, triggered NF-κB-signaling, and amplified TCR-driven functional activation of engineered T cells, particularly against targets with lower antigen density. In a patient-derived orthotropic xenograft model of aggressive, incurable thyroid cancer, autologous ICCR+ T cells showed selective expansion and prolongation of survival. ICCR+ T cells exhibited reduced TCR diversity, and upregulation of cytotoxicity, TCR signaling, costimulation, and exhaustion genes.

Contributed by Ute Burkhardt

ABSTRACT: Engineered T cell therapies, such as chimeric antigen receptor (CAR) and T cell receptor (TCR)-based approaches, have transformed outcomes in hematological malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFN_ released during early T cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NF_B signaling independently of TCR-p/MHC engagement; however, full T cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T cell responses in solid tumor microenvironments.

Author Info: (1) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (2) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (3) Weill Corn

Author Info: (1) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (2) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (3) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (4) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (5) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (6) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (7) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (8) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (9) AffyImmune Therapeutics, Inc. Natick, MA United States. (10) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (11) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (12) Houston Methodist Research Institute Houston, TX United States. (13) Weill Cornell Medicine New York, New York United States. ROR: https://ror.org/02r109517 (14) Weill Cornell Medicine New York, New York United States. ROR: https://ror.org/02r109517 (15) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (16) New York Presbyterian Hospital - Weill Cornell Medical College New York, NY United States. (17) Weill Cornell New York, NY United States. (18) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171

Citation: Cancer Immunol Res 2026 Apr 27 Epub04/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42043451

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Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance

(1) Lei G (2) Lu Z (3) Xu Z (4) Braun C (5) Huo D (6) Gao J (7) Tan L (8) Hong T (9) Wu S (10) Sun M (11) Zhao X (12) Li Q (13) Chen X (14) Yan Y (15) Lee H (16) Mao C (17) Zhuang L (18) Ku LT (19) Puebla N (20) Barsoumian H (21) Yao J (22) Hong L (23) Zhang J (24) Tran H (25) Lee JJ (26) Gibbons D (27) Vaporciyan A (28) Heymach J (29) Lin C (30) Gottlieb E (31) You MJ (32) Welsh JW (33) Lin SH (34) Zang X (35) Li Z (36) Gan B

Cell

Lei, Lu, and Xu et al. showed that cuproptosis induced immunogenic cell death, releasing DAMPs that drove DC maturation, DC-dependent cross-priming, and M1-like TAM and effector CD8+ T cell remodeling, with enhanced tumor suppression in immunocompetent hosts. CD8+ T cell-derived IFNγ activated STAT1–IRF1 signaling to upregulate mitochondrial FDX1 in tumor cells, increasing protein lipoylation and sensitization to cuproptosis. In breast, lung, and pancreatic tumor models, combining cuproptosis inducers with anti-PD-L1 amplified tumoral cuproptosis, increased intratumoral CD8+ T cell functions, and overcame intrinsic and acquired ICB resistance.

Contributed by Shishir Pant

(1) Lei G (2) Lu Z (3) Xu Z (4) Braun C (5) Huo D (6) Gao J (7) Tan L (8) Hong T (9) Wu S (10) Sun M (11) Zhao X (12) Li Q (13) Chen X (14) Yan Y (15) Lee H (16) Mao C (17) Zhuang L (18) Ku LT (19) Puebla N (20) Barsoumian H (21) Yao J (22) Hong L (23) Zhang J (24) Tran H (25) Lee JJ (26) Gibbons D (27) Vaporciyan A (28) Heymach J (29) Lin C (30) Gottlieb E (31) You MJ (32) Welsh JW (33) Lin SH (34) Zang X (35) Li Z (36) Gan B

Cell

Lei, Lu, and Xu et al. showed that cuproptosis induced immunogenic cell death, releasing DAMPs that drove DC maturation, DC-dependent cross-priming, and M1-like TAM and effector CD8+ T cell remodeling, with enhanced tumor suppression in immunocompetent hosts. CD8+ T cell-derived IFNγ activated STAT1–IRF1 signaling to upregulate mitochondrial FDX1 in tumor cells, increasing protein lipoylation and sensitization to cuproptosis. In breast, lung, and pancreatic tumor models, combining cuproptosis inducers with anti-PD-L1 amplified tumoral cuproptosis, increased intratumoral CD8+ T cell functions, and overcame intrinsic and acquired ICB resistance.

Contributed by Shishir Pant

ABSTRACT: Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8(+) T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8(+) T cell-derived interferon (IFN)-_ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.

Author Info: (1) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: guanglei_csu@163.com. (2) Departme

Author Info: (1) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: guanglei_csu@163.com. (2) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7) Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (12) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (14) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (15) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (16) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (17) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (18) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (19) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (20) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (23) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (24) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (25) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (26) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (27) Department of Thoracic and Cardiovascular Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (28) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (29) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (30) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (31) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. (32) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (33) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (34) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (35) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (36) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: bgan@mdanderson.org.

Citation: Cell 2026 Jun 22 Epub06/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42330950

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TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.

Contributed by Paula Hochman

(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X

Cell reports. Medicine

To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.

Contributed by Paula Hochman

ABSTRACT: The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named _TIGIT-IL12 (T-12), which fuses the 13G6 (_TIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8(+) T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8(+) T cells. T-12 preferentially activates tumor-infiltrating NK and CD8(+) T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedic

Author Info: (1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, Guangxi, China. (3) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (4) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. (8) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: mahongdi@ustc.edu.cn. (9) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: tzg@ustc.edu.cn. (10) Department of Immunology, School of Basic Medical Sciences, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: haoyusun@ustc.edu.cn. (11) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: ustczxh@ustc.edu.cn.

Citation: Cell Rep Med 2026 Jun 16 102876 Epub06/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42302794

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Neutrophil regulation of immunotherapy for cancer is controlled by type II interferon

(1) Pei S (2) Pan Y (3) Liang H (4) Lei L (5) Lin Q (6) Mi J (7) Ravetch JV (8) Soehnlein O (9) Karlsson MCI

Immunity

Pei et al. found that the IFNγ produced in tumors during treatment with various immunotherapies induced PD-L1 expression by neutrophils and drove them towards an aged/immunosuppressive phenotype, which contributed to treatment resistance. This could be alleviated by eliminating neutrophils or disrupting type II IFN signaling or PD-L1 expression, which shifted neutrophil polarization to a more pro-inflammatory state. The accumulation of aged, PD-L1+ neutrophils was also evident in data from immunotherapy-treated human tumors, suggesting possible avenues for intervention to improve immunotherapy responses.

(1) Pei S (2) Pan Y (3) Liang H (4) Lei L (5) Lin Q (6) Mi J (7) Ravetch JV (8) Soehnlein O (9) Karlsson MCI

Immunity

Pei et al. found that the IFNγ produced in tumors during treatment with various immunotherapies induced PD-L1 expression by neutrophils and drove them towards an aged/immunosuppressive phenotype, which contributed to treatment resistance. This could be alleviated by eliminating neutrophils or disrupting type II IFN signaling or PD-L1 expression, which shifted neutrophil polarization to a more pro-inflammatory state. The accumulation of aged, PD-L1+ neutrophils was also evident in data from immunotherapy-treated human tumors, suggesting possible avenues for intervention to improve immunotherapy responses.

ABSTRACT: Tumor resistance to immunotherapy is driven by several mechanisms, including those imposed by myeloid populations. Neutrophils are prominent within this landscape and display functional heterogeneity. Here, we investigated the contextual role of neutrophils, and using neutropenic mice, we found that the dominating function was to block the response when targeting T cells or myeloid cells. We found that neutrophils upregulated programmed death ligand-1 (PD-L1) in response to the treatment and, using this as a target, depleted this population. The upregulation of PD-L1 was dependent on interferon-γ (IFN-γ) produced by cytotoxic lymphocytes. Specific genetic deletion of cd274 or Ifngr1 on neutrophils showed that this was cell intrinsic. Moreover, in the absence of the capacity for specific IFN-γ-driven suppression, neutrophils changed their phenotype to support immunotherapy. Thus, we find that the type II interferon, IFN-γ, is key in determining whether neutrophils will support or block immunotherapy for cancer.

Author Info: (1) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. (2) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Sto

Author Info: (1) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. (2) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. (3) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. (4) Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. (5) Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. (6) Department of Gastroenterology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. (7) Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, USA. (8) University of Munster, Institute of Experimental Pathology, Munster, Germany. (9) Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address: mikael.karlsson@ki.se.

Citation: Immunity 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42296966

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The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

ABSTRACT: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicin

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (5) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (9) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (13) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (14) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (17) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (18) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France. (19) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (20) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Clinical Immunology Laboratory, Institut Curie, Paris, France. (23) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (24) Department of Translational Research, PSL University, Institut Curie, Paris, France; INSERM U1330, PSL University, Institut Curie Research Center, Paris, France. (25) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (26) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France; Clinical Hematology Unit, Institut Curie, Saint-Cloud, France. (27) Departments of Dermatology and Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (29) Kite, a Gilead Company, Santa Monica, CA, USA. (30) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (31) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (32) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (33) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (34) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (35) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. (37) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (38) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (39) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (40) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (41) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (42) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (43) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (44) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (45) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (46) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (47) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (48) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: binderz@pennmedicine.upenn.edu. (49) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Clinical Laboratory, H™pital Foch, Suresnes, France. Electronic address: c.alanio@hopital-foch.com. (50) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dana.silverbush@pennmedicine.upenn.edu.

Citation: Cell 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42296961

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Integration of donor microbiota following FMT correlates with anti-PD-1 response in melanoma Spotlight 

(1) Fessler JL (2) Olm MR (3) Engleman EG (4) Sonnenburg JL

Nature communications

Using data from three trials of FMT plus anti-PD-1 in melanoma, Fessler et al. performed a strain-resolved metagenomic meta-analysis, and found that while neither microbial diversity nor acquisition of specific bacterial species were associated with response, recipient acquisition of the donor microbiome and microbiome community stability were. Further, while non-responders were enriched for pro-inflammatory and pathogen-associated secretion system genes, responders were enriched for functions of community-level metabolism and communication, highlighting the importance of the microbial ecosystem over species richness or specific species.

Contributed by Lauren Hitchings

(1) Fessler JL (2) Olm MR (3) Engleman EG (4) Sonnenburg JL

Nature communications

Using data from three trials of FMT plus anti-PD-1 in melanoma, Fessler et al. performed a strain-resolved metagenomic meta-analysis, and found that while neither microbial diversity nor acquisition of specific bacterial species were associated with response, recipient acquisition of the donor microbiome and microbiome community stability were. Further, while non-responders were enriched for pro-inflammatory and pathogen-associated secretion system genes, responders were enriched for functions of community-level metabolism and communication, highlighting the importance of the microbial ecosystem over species richness or specific species.

Contributed by Lauren Hitchings

ABSTRACT: Fecal microbiota transplantation (FMT) has shown promise in improving anti-PD-1 therapy in melanoma, but the underlying microbial features remain poorly defined. We performed a strain-resolved metagenomic meta-analysis across three independent FMT plus anti-PD-1 melanoma trials (n_=_41). Across cohorts, therapeutic benefit was linked to successful integration of donor microbiota, rather than increased diversity or engraftment of specific species. Responders acquired more donor-derived strains, exhibited greater post-FMT similarity to their donor, and maintained a more stable microbiome. Following FMT, non-responders' microbiomes showed greater taxonomic instability, larger fluctuations in estimated microbial load, and increased abundance of pathogen-associated secretion system genes, whereas responders showed enrichment for microbial functions involved in community-level metabolism and communication. Finally, shifts in tumor-infiltrating immune profiles tracked with clinical outcomes and microbiome changes. Together these findings highlight that distinct patterns of microbiome restructuring, including stable community transitions and altered functional capacity, are associated with anti-PD-1 response following FMT.

Author Info: (1) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Integrative Physiology, University of Colorado Boulder,

Author Info: (1) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA. (4) Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. jsonnenburg@stanford.edu. Chan Zuckerberg Biohub, San Francisco, CA, USA. jsonnenburg@stanford.edu. Center for Human Microbiome Studies, Stanford University School of Medicine, Stanford, CA, USA. jsonnenburg@stanford.edu.

Citation: Nat Commun 2026 May 30 Epub05/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42218119

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Immunoediting restricts clonal neoantigens in primary, treatment-naive human tumors Spotlight 

(1) Borden ES (2) Castellano D (3) Kantzos EA (4) Hughes A (5) Leibovit-Reiben Z (6) Stockard A (7) Choudhary A (8) Ma T (9) Li X (10) Mangold AR (11) Gutenkunst RN (12) LaFleur BJ (13) Buetow KH (14) Wilson MA (15) Hastings KT

Immunity

To investigate immunoediting in human tumors, Borden et al. analyzed primary, treatment-naive cSCC tumors, which frequently arise in immunosuppressed patients following solid organ transplant, suggesting immune involvement. Compared to tumors from immunodeficient patients or just poorly infiltrated tumors, tumors from immunocompetent patients with high infiltration showed lower overall and clonal mutation burdens, and a lower frequency of variant alleles with high predicted neoantigen:MHC-I binding affinity. Further, neoantigens that shared features with validated immunogenic neoantigens were decreased in clonal versus subclonal cancer cells.

Contributed by Lauren Hitchings

(1) Borden ES (2) Castellano D (3) Kantzos EA (4) Hughes A (5) Leibovit-Reiben Z (6) Stockard A (7) Choudhary A (8) Ma T (9) Li X (10) Mangold AR (11) Gutenkunst RN (12) LaFleur BJ (13) Buetow KH (14) Wilson MA (15) Hastings KT

Immunity

To investigate immunoediting in human tumors, Borden et al. analyzed primary, treatment-naive cSCC tumors, which frequently arise in immunosuppressed patients following solid organ transplant, suggesting immune involvement. Compared to tumors from immunodeficient patients or just poorly infiltrated tumors, tumors from immunocompetent patients with high infiltration showed lower overall and clonal mutation burdens, and a lower frequency of variant alleles with high predicted neoantigen:MHC-I binding affinity. Further, neoantigens that shared features with validated immunogenic neoantigens were decreased in clonal versus subclonal cancer cells.

Contributed by Lauren Hitchings

ABSTRACT: T cell targeting of cancer cells alters the tumor antigen landscape in preclinical models. Here, we examined the impact of immunoediting on the antigenic landscape of primary, treatment-naive human tumors. Cutaneous squamous cell carcinoma tumors from immunocompetent and immunosuppressed patients revealed consistent tumor mutational signatures; however, high-immune-infiltrate tumors from immunocompetent patients had lower overall mutational burdens and lower clonal mutational burdens compared with low-infiltrate tumors from immunocompetent patients and tumors from immunosuppressed patients. The lower clonal mutational burden in high-immune-infiltrate tumors from immunocompetent patients persisted after accounting for tumor purity and growth rate. Predicted neoantigen: major histocompatibility complex (MHC) class I binding affinity decreased with increasing variant allele frequency, demonstrating restriction of mutations encoding MHC-binding neoantigens. Neoantigens with features shared with validated immunogenic neoantigens were decreased in clonal relative to subclonal cancer cell populations in high-immune-infiltrate tumors from immunocompetent patients. Thus, the immune system restricts cancer cells expressing immunogenic antigens from clonal populations in primary, treatment-naive human tumors.

Author Info: (1) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA. (2)

Author Info: (1) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA. (2) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA. (3) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA. (4) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (5) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (6) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (7) Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Champaign, IL 61801, USA. (8) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (9) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (10) Department of Dermatology, Mayo Clinic Health System, Scottsdale, AZ 85259, USA. (11) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA. (12) BIO5 Institute, University of Arizona, Tucson, AZ 85719, USA; R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA. (13) School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA; Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281, USA. (14) School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA; Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281, USA. (15) Department of Dermatology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85719, USA. Electronic address: khasting@arizona.edu.

Citation: Immunity 2026 Jun 11 Epub06/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42276071

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MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial Spotlight 

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C

Nature medicine

In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.

Contributed by Alex Najibi

ABSTRACT:IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401 (0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14% (8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% (8/41) was observed across 15 different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D, namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) CharitŽ UniversitŠtsmedizin Berlin, Berlin, Germany. (3)

Author Info: (1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) CharitŽ UniversitŠtsmedizin Berlin, Berlin, Germany. (3) National Center for Tumor Diseases, Heidelberg, Germany. (4) Department of Hematology, Oncology, and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. (5) Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. (6) National Center for Tumor Diseases, Heidelberg, Germany. Thoraxklinik Heidelberg gGmbH, University Hospital Heidelberg, Heidelberg, Germany. (7) University Hospital WŸrzburg, Comprehensive Cancer Center Mainfranken, WŸrzburg, Germany. (8) Marien Hospital DŸsseldorf, DŸsseldorf, Germany. (9) Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany. (10) Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, School of Medicine and Health, Munich, Germany. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich (TUM), Munich, Germany. (11) University Hospital of TŸbingen, TŸbingen, Germany. (12) University Hospital Regensburg, Regensburg, Germany. (13) Immatics Biotechnologies GmbH, TŸbingen, Germany. (14) Immatics Biotechnologies GmbH, TŸbingen, Germany. (15) Immatics Biotechnologies GmbH, TŸbingen, Germany. (16) Immatics Biotechnologies GmbH, TŸbingen, Germany. (17) Immatics Biotechnologies GmbH, TŸbingen, Germany. (18) Immatics Biotechnologies GmbH, TŸbingen, Germany. (19) Immatics Biotechnologies GmbH, TŸbingen, Germany. (20) Immatics Biotechnologies GmbH, TŸbingen, Germany. (21) University Hospital Bonn, Bonn, Germany. (22) Nuremberg General Hospital, Nuremberg, Germany. (23) Department of Otorhinolaryngology and Head & Neck Surgery, Ulm University Medical Center, Ulm, Germany. (24) University Hospital, Goethe University Frankfurt, Frankfurt Cancer Institute, Frankfurt, Germany. (25) University Hospital Erlangen, Erlangen, Germany. (26) Immatics Biotechnologies GmbH, TŸbingen, Germany. (27) Immatics Biotechnologies GmbH, TŸbingen, Germany. Carsten.Reinhardt@immatics.com.

Citation: Nat Med 2026 May 31 Epub05/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42219399

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