Journal Articles

CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells

(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD

Cancer immunology research

Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.

(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD

Cancer immunology research

Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.

ABSTRACT: It is well established that CD4⁺ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8⁺ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4⁺ T cells are essential not only during T-cell priming, but also to maintain T-cell effector function within the tumor. Depleting CD4⁺ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8⁺ T cells and their intratumoral accumulation. CD4⁺ T cells were required for functional reinvigoration of CD8⁺ tumor-infiltrating lymphocytes (TIL) by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4⁺ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming, but rather depended on IL-2 and IFNγ. Using a TCR-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Aᵇ complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4⁺ T-cell help after priming. These findings reveal temporally distinct requirements for CD4⁺ T-cell help and establish a need for continuous CD4⁺/CD8⁺ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.

Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://

Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (3) Washington University in St Louis St Louis United States. (4) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (5) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (6) Washington University in St. Louis United States. ROR: https://ror.org/01yc7t268 (7) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (8) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (9) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (10) Washington University in St. Louis Saint Louis, MO United States. ROR: https://ror.org/01yc7t268 (11) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (12) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (13) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (14) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (15) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (16) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268

Citation: Cancer Immunol Res 2026 Jul 16 Epub07/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462143

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Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma

(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) MulŽ JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S

Med | Free PMC Article

Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.

Contributed by Shishir Pant

(1) Karapetyan L (2) Xu J (3) Ward K (4) Kalos D (5) Schachner B (6) Ali J (7) Song X (8) Kuriakose J (9) Hall MS (10) Chau J (11) Cox CA (12) Al-Bzour AN (13) Falahat R (14) Perez MC (15) Mullinax JE (16) Zager JS (17) Gonzalez R (18) Sondak VK (19) Tsai KY (20) Messina JL (21) Moran-Segura C (22) Lopez-Blanco N (23) Alleyne AE (24) Nguyen JV (25) Schell MJ (26) Markowitz J (27) Brohl AS (28) Eroglu Z (29) Tarhini AA (30) Khushalani NI (31) Hwu P (32) MulŽ JJ (33) Sarnaik AA (34) Beatty MS (35) Pilon-Thomas S

Med | Free PMC Article

Karapetyan et al. profiled TIL infusion products and matched TIMEs from patients with metastatic melanoma treated on TIL-based trials with or without ICB or BRAFi, and found that responders had infusion products enriched for stem-like memory and LAG3+ CD8+ TILs with enhanced peripheral persistence. Multiplex IF and spatial transcriptomics identified TLSs and immune transcriptomic features, such as antigen presentation, IFN signaling, B cell activation, and chemokine pathways in TIL responders. Prior ICB exposure reduced CD8+ stem-like TILs, co-stimulatory receptor expression, and TCR diversity, consistent with impaired TIL fitness.

Contributed by Shishir Pant

BACKGROUND: The immunologic features of tumor-infiltrating lymphocyte (TIL) infusion products and their interactions with the tumor microenvironment that govern clinical responses in metastatic melanoma remain incompletely characterized. METHODS: We performed integrated immunophenotypic and spatial transcriptomic profiling of TIL infusion products and matched tumor microenvironments from patients treated on early-phase clinical trials. RESULTS: The durable objective response rate was 36%, with a median progression-free survival of 8 months among patients treated with TIL therapy with or without additional therapies. Responders exhibited infusion products enriched for CD8(+) T cells, stem-like memory subsets, and LAG-3-expressing CD8(+) T cells, together with enhanced peripheral TIL persistence. The abundance of infused LAG-3+ TILs correlated with tumor reactivity and prolonged progression-free survival. Prior immune checkpoint inhibitor exposure was associated with reduced CD8(+) stem cell memory T cell frequency and diminished co-stimulatory receptor expression, suggesting impaired TIL fitness. Tumors enriched for tertiary lymphoid structures and spatial immune programs characterized by antigen presentation, interferon signaling, and B cell activation were independently associated with clinical benefit. CONCLUSIONS: These findings define an integrated framework linking TIL composition and the tumor microenvironment to therapeutic response and identify potential biomarkers and biological features that may guide patient selection and optimization of TIL therapy. FUNDING: This work was funded by Iovance Biotherapeutics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence, American Cancer Society-Leo and Anne Albert Charitable Foundation Research Scholar Grant, and Melanoma SPORE (P50CA168536).

Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School

Author Info: (1) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: lilit.karapetyan@moffitt.org. (2) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (3) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (8) Department of Molecular Biosciences, University of South Florida, Tampa, FL 33612, USA. (9) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (10) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (11) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (12) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (13) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (14) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (15) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (16) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (17) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (18) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (19) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (20) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (21) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (22) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (23) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (24) Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (25) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (26) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (27) Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (28) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (29) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (30) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA. (31) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (32) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. (33) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: amod.sarnaik@moffitt.org. (34) Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: matthew.beatty@moffitt.org. (35) Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Immuno-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Translational Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: shari.pilon-thomas@moffitt.org.

Citation: Med 2026 Jul 29 101231 Epub07/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42526429

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Tumor-specific antibodies elicited by engineered bacteria promote bladder cancer immunotherapy in preclinical mouse models

(1) Rouanne M (2) Chen N (3) Mariuzza DL (4) Yang Z (5) Li F (6) de Los Santos-Alexis K (7) Savage TM (8) Vincent RL (9) Mendelsohn CL (10) Danino T (11) Arpaia N

Science translational medicine

Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.

Contributed by Paula Hochman

(1) Rouanne M (2) Chen N (3) Mariuzza DL (4) Yang Z (5) Li F (6) de Los Santos-Alexis K (7) Savage TM (8) Vincent RL (9) Mendelsohn CL (10) Danino T (11) Arpaia N

Science translational medicine

Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.

Contributed by Paula Hochman

ABSTRACT: The intratumoral microbiome has recently emerged as a potential hallmark of cancer, with implications for response or resistance to therapy. Bacteria can either promote or inhibit cancer growth. However, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment. Here, we engineered the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to express the human chemokine CXCL13 (C-X-C motif chemokine ligand 13), a critical component of germinal center (GC) formation. Antibody affinity maturation and class switching are fundamental aspects of adaptive immune response. Both occur primarily in the GCs of secondary lymphoid organs for defense against pathogens. Immune checkpoint blockade (ICB) efficacy is primarily driven by T cells; however, recent studies in mice and humans have shown that humoral immune responses act as critical partners for ICB-mediated antitumor activity. Using orthotopic models of bladder cancer, intravesically delivered engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor-draining lymph nodes after intravesical delivery. When combined with programmed cell death protein 1 (PD-1) blockade, engineered EcN improved antitumor activity in two aggressive, fast-growing, and immunologically cold orthotopic mouse models of bladder cancer. Mechanistically, this antitumor effect was dependent on the presence of CD8(+) T cells and CD4(+) T follicular helper cells; combination therapy increased tumor-specific antibody responses and promoted long-term survival and protective immunity upon tumor rechallenge. Thus, we demonstrate that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (2) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (3) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (4) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (5) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (6) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (7) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (9) Department of Urology, Columbia University, New York, NY 10032, USA. (10) Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Data Science Institute, Columbia University, New York, NY 10027, USA. (11) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Citation: Sci Transl Med 2026 Jul 22 18:eadv7600 Epub07/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42485436

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Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models

(1) Lin HK (2) Blake DA (3) Freeman R (4) Chen Y (5) Kim J (6) Johnson AM (7) Wells K (8) Mudigonda A (9) Liu W (10) Yadav P (11) Zeng F (12) Muhuri A (13) Min K (14) Sarkar S (15) Wang Y (16) Goyal S (17) Roberts RC (18) Christensen E (19) Ward AB (20) Heller B (21) Chun P (22) Dougan J (23) Porter CC (24) Barwick BG (25) Paulos CM (26) Yang L (27) Patgiri A (28) Thomas SN (29) Waller EK (30) Rafiq S

Science translational medicine

Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.

Contributed by Ute Burkhardt

(1) Lin HK (2) Blake DA (3) Freeman R (4) Chen Y (5) Kim J (6) Johnson AM (7) Wells K (8) Mudigonda A (9) Liu W (10) Yadav P (11) Zeng F (12) Muhuri A (13) Min K (14) Sarkar S (15) Wang Y (16) Goyal S (17) Roberts RC (18) Christensen E (19) Ward AB (20) Heller B (21) Chun P (22) Dougan J (23) Porter CC (24) Barwick BG (25) Paulos CM (26) Yang L (27) Patgiri A (28) Thomas SN (29) Waller EK (30) Rafiq S

Science translational medicine

Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.

Contributed by Ute Burkhardt

ABSTRACT: Clinical efficacy with chimeric antigen receptor (CAR) T cells is currently limited by numerous factors including poor initial product phenotypes and lack of engagement of endogenous immunity. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide, and the antagonism of its receptor (VIPR) on T cells potentiates T cell activation. We demonstrated that VIP suppresses CAR T cell function and engineered CAR T cells to secrete a short peptide drug that antagonizes VIPR (CAR/VIPRa). Armored CAR/VIPRa T cells maintained a memory phenotype and were metabolically quiescent after manufacturing yet mounted a strong bioenergetic response after antigen stimulation. Moreover, CAR/VIPRa T cells potentiated endogenous antitumor immunity through the recruitment of host T cells. In syngeneic and xenogeneic mouse models of hematological and solid tumors, CAR/VIPRa T cells exhibited greater tumor infiltration and maintained a less exhausted memory phenotype, resulting in superior antitumor efficacy. Together, these data show that VIPRa peptides produced by armored CAR T cells can enhance T cell function and boost endogenous immunity, thereby improving tumor control.

Author Info: (1) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Hematology and Medical Oncology, Emory University School

Author Info: (1) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (3) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (4) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (5) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (6) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (9) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (10) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (11) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (12) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (13) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (14) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (15) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (16) Biostatistics Shared Resource, Emory University School of Medicine, Atlanta, GA, USA. (17) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (18) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (19) Cambium Oncology, Atlanta, GA, USA. (20) Achieve Clinics, Los Angeles, CA, USA. (21) Achieve Clinics, Los Angeles, CA, USA. Eldred Advisors, Los Angeles, CA, USA. (22) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. (23) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA. (24) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (25) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (26) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (27) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (28) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. (29) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (30) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA.

Citation: Sci Transl Med 2026 Jul 22 18:eadt9565 Epub07/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42485431

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Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells

(1) Nagler A (2) Sud A (3) Ghannam JY (4) Pomerance L (5) Robles-Oteiza C (6) Afeyan AB (7) Weir JA (8) Russell AJC (9) Lu WS (10) Van Orden M (11) Sonnenholzner A (12) Marrero GJ (13) Gong Q (14) Kumar V (15) Huang K (16) Tu C (17) Lin E (18) Shim B (19) De Oliveira GR (20) Sellars MC (21) Yoon CH (22) Reardon DA (23) Choueiri TK (24) Olsen LR (25) Signoretti S (26) Ott PA (27) Braun DA (28) Oliveira G (29) Li S (30) Livak KJ (31) Hacohen N (32) Chen F (33) Wu CJ

Nature biotechnology

Nagler, Sud, and Ghannam et al. developed a droplet-based single-nucleus spatial transcriptomics platform, Slide-GoTags, that integrates genotyping, TCR sequencing, and snRNAseq from the same frozen section to map neoantigen-specific immunity in situ. Slide-GoTags showed spatial co-localization of neoantigen-expressing tumor cells and their cognate T cell clonotypes, and distinct ICB-driven spatial immune landscapes. In melanoma, ccRCC, GBM, and ovarian cancer, Slide-GoTags identified IFN-driven niches enriched in activated or progenitor T cell clonotypes, with three TCR-neoantigen pairs in immunologically hot tumors.

Contributed by Shishir Pant

(1) Nagler A (2) Sud A (3) Ghannam JY (4) Pomerance L (5) Robles-Oteiza C (6) Afeyan AB (7) Weir JA (8) Russell AJC (9) Lu WS (10) Van Orden M (11) Sonnenholzner A (12) Marrero GJ (13) Gong Q (14) Kumar V (15) Huang K (16) Tu C (17) Lin E (18) Shim B (19) De Oliveira GR (20) Sellars MC (21) Yoon CH (22) Reardon DA (23) Choueiri TK (24) Olsen LR (25) Signoretti S (26) Ott PA (27) Braun DA (28) Oliveira G (29) Li S (30) Livak KJ (31) Hacohen N (32) Chen F (33) Wu CJ

Nature biotechnology

Nagler, Sud, and Ghannam et al. developed a droplet-based single-nucleus spatial transcriptomics platform, Slide-GoTags, that integrates genotyping, TCR sequencing, and snRNAseq from the same frozen section to map neoantigen-specific immunity in situ. Slide-GoTags showed spatial co-localization of neoantigen-expressing tumor cells and their cognate T cell clonotypes, and distinct ICB-driven spatial immune landscapes. In melanoma, ccRCC, GBM, and ovarian cancer, Slide-GoTags identified IFN-driven niches enriched in activated or progenitor T cell clonotypes, with three TCR-neoantigen pairs in immunologically hot tumors.

Contributed by Shishir Pant

ABSTRACT: Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.

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

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard/MIT MD-PhD Program and Harvard Immunology PhD Program, Harvard Medical School, Boston, MA, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (11) LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Molecular Imaging Core (MIC), Dana-Farber Cancer Institute, Boston, MA, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (24) Department of Bio and Health Informatics, Technical University of Denmark, Copenhagen, Denmark. Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark. (25) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (27) Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (31) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (32) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu. Division of Stem Cell Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu.

Citation: Nat Biotechnol 2026 Jul 22 Epub07/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42486969

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Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies

(1) Meyerhoff RR (2) Chen A (3) O'Brien J (4) Anadon CM (5) Lopez Bailon LU (6) Carrion-Estrada D (7) Poysungnoen K (8) Lindenberger J (9) Kemeny G (10) Lyniv L (11) Jain V (12) Chaurio R (13) Plappert N (14) Evangelous T (15) Park CS (16) Sinha A (17) Oduah E (18) Glass C (19) Weinhold K (20) Gregory S (21) Hickey JW (22) Acharya P (23) Ready N (24) Conejo-Garcia JR (25) Williams WB (26) Antonia SJ

Cancer cell

Evaluating patient NSCLC tumors treated with neoadjuvant anti-PD-1 and enriched for tertiary lymphoid structures, Meyerhoff, Chen, and O’brien et al. used transcriptomic data to identify B cell populations, including CD138+ plasma cells, and then performed single-cell sequencing to identify tumor-targeting BCRs and generate recombinant antibodies. The lead antibody, PC-1, recognized citrullinated antigens on tumor and pro-tumor myeloid cells, dependent on their expression of the citrullination enzyme PAD2. Incorporation of PC-1 into a CAR T cell mediated tumor control in mouse models, without evidence of off-tumor toxicity.

Contributed by Lauren Hitchings

(1) Meyerhoff RR (2) Chen A (3) O'Brien J (4) Anadon CM (5) Lopez Bailon LU (6) Carrion-Estrada D (7) Poysungnoen K (8) Lindenberger J (9) Kemeny G (10) Lyniv L (11) Jain V (12) Chaurio R (13) Plappert N (14) Evangelous T (15) Park CS (16) Sinha A (17) Oduah E (18) Glass C (19) Weinhold K (20) Gregory S (21) Hickey JW (22) Acharya P (23) Ready N (24) Conejo-Garcia JR (25) Williams WB (26) Antonia SJ

Cancer cell

Evaluating patient NSCLC tumors treated with neoadjuvant anti-PD-1 and enriched for tertiary lymphoid structures, Meyerhoff, Chen, and O’brien et al. used transcriptomic data to identify B cell populations, including CD138+ plasma cells, and then performed single-cell sequencing to identify tumor-targeting BCRs and generate recombinant antibodies. The lead antibody, PC-1, recognized citrullinated antigens on tumor and pro-tumor myeloid cells, dependent on their expression of the citrullination enzyme PAD2. Incorporation of PC-1 into a CAR T cell mediated tumor control in mouse models, without evidence of off-tumor toxicity.

Contributed by Lauren Hitchings

ABSTRACT: The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138(+) plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.

Author Info: (1) Division of Interventional Radiology, Department of Radiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: meyerhr@mskcc.org. (2) Division of

Author Info: (1) Division of Interventional Radiology, Department of Radiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: meyerhr@mskcc.org. (2) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (3) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (4) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (5) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (6) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (7) Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA. (8) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (9) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (10) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (11) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (12) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (13) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (14) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. (15) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (16) Department of Chemistry, Duke University, Durham, NC 27710, USA; Department of Computer Science, Duke University, Durham, NC 27710, USA. (17) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (18) Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA. (19) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA. (20) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (21) Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. (22) Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. (23) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. (24) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA. (25) Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: wilton.williams@duke.edu. (26) Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: scott.antonia@duke.edu.

Citation: Cancer Cell 2026 Jul 27 Epub07/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42508408

Tags:

Tertiary lymphoid structures harbour stem-like tumour-specific T cells

(1) Afeyan AB (2) Nagler A (3) Tu CR (4) Roberti De Oliveira G (5) Simsek B (6) Seager MD (7) El Ahmar N (8) Sax HE (9) Lin E (10) Sud A (11) Borji M (12) Forman C (13) Liu S (14) Ott PA (15) Choueiri TK (16) Abelin JG (17) Burack R (18) Li S (19) Livak KJ (20) Tyekucheva S (21) Keskin DB (22) Chen F (23) Atkins MB (24) Simon JM (25) Signoretti S (26) Oliveira G (27) Braun DA (28) Wu CJ

Nature

Afeyan, Nagler, and Tu et al. investigated how tertiary lymphoid structures (TLSs) impact phenotypic properties of tumor-specific T cells in treatment-naive renal carcinoma (RCC). Compared to TLS- tumors, TLS+ tumors were associated with increased numbers of exhausted CD8+ T cells (Tex) as well as IFN-stimulated CD8+ T cells and proliferating T cells, although CD8+ T cells exhibited greater exhaustion in TLS- tumors. 12% of tumor-specific clonotypes in TLSs exhibited a stem-like progenitor exhausted phenotype (Tpex) associated with favorable antitumor immunity. CD163+ immunosuppressive TAMs mapped to TLS boundaries with Tex cells.

Contributed by Katherine Turner

(1) Afeyan AB (2) Nagler A (3) Tu CR (4) Roberti De Oliveira G (5) Simsek B (6) Seager MD (7) El Ahmar N (8) Sax HE (9) Lin E (10) Sud A (11) Borji M (12) Forman C (13) Liu S (14) Ott PA (15) Choueiri TK (16) Abelin JG (17) Burack R (18) Li S (19) Livak KJ (20) Tyekucheva S (21) Keskin DB (22) Chen F (23) Atkins MB (24) Simon JM (25) Signoretti S (26) Oliveira G (27) Braun DA (28) Wu CJ

Nature

Afeyan, Nagler, and Tu et al. investigated how tertiary lymphoid structures (TLSs) impact phenotypic properties of tumor-specific T cells in treatment-naive renal carcinoma (RCC). Compared to TLS- tumors, TLS+ tumors were associated with increased numbers of exhausted CD8+ T cells (Tex) as well as IFN-stimulated CD8+ T cells and proliferating T cells, although CD8+ T cells exhibited greater exhaustion in TLS- tumors. 12% of tumor-specific clonotypes in TLSs exhibited a stem-like progenitor exhausted phenotype (Tpex) associated with favorable antitumor immunity. CD163+ immunosuppressive TAMs mapped to TLS boundaries with Tex cells.

Contributed by Katherine Turner

ABSTRACT: Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours(1,2), but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8(+) T cells and have a reduced terminal exhaustion transcriptional program compared with TLS(-) tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer I

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (5) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (6) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (7) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Ragon Institute of MGB, MIT and Harvard, Cambridge, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (17) University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, Rochester, NY, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA. Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (23) Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. (24) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. giacomo_oliveira@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. giacomo_oliveira@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. giacomo_oliveira@dfci.harvard.edu. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. david.braun@yale.edu. Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. david.braun@yale.edu. Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. david.braun@yale.edu. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu.

Citation: Nature 2026 Jul 22 Epub07/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42486979

Tags:

Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy

Spotlight 

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

ABSTRACT: Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compen- sated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased sMAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de rec

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de recherche Du CHUM (CRCHUM), Montréal, QC H2W1T8, Canada. 3- Centre de Recherche des Cordeliers, INSERM U1138, Equipe Labellisée – Ligue Nationale Contre le Cancer, Université Paris Cité, Sorbonne Université, 75006 Paris, France. 4- Unidad de Excelencia, Instituto de Biomedicina y Genética Molecular de Valladolid, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, 47001 Valladolid, Spain. 5- MetaGenoPolis, INRAe, Université Paris-Saclay 78350 Jouy en Josas, France. 6- Université Paris-Saclay, INSERM US23, Analyse moléculaire, modélisation et imagerie de la maladie Cancéreuse, Plateformes de Métabolomique et de Criblage Cellulaire Haut Débit, 94805 Villejuif, France. 7- Université Paris-Saclay, Gustave Roussy, U1356 Next Generation Immuno-Oncology Research, 94805 Villejuif, France

Citation: Cancer Cell July 2026

Tags:

    A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners Spotlight 

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    ABSTRACT: Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small molecule screen on primary TAMs isolated directly from GBM patient tumors, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations, and synergized with CD47 blockade ex vivo. In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA-sequencing and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-κB activation, and epigenetic priming of FcγR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM-reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San F

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San Francisco San Francisco United States. ROR: https://ror.org/043mz5j54 (4) University of California San Francisco Medical Center San Francisco United States. ROR: https://ror.org/01t8svj65 (5) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (6) Stanford University California 94305-5439, CA United States. ROR: https://ror.org/00f54p054 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (9) Stanford University Stanford University, CA United States. ROR: https://ror.org/00f54p054

    Citation: Cancer Immunol Res 2026 Jul 14 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42446904

    Tags:

    Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy Spotlight 

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    ABSTRACT: Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (5) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (6) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (7) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (8) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (9) University of Pittsburgh Pittsburgh, PA United States. (10) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (11) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (12) University of North Carolina Hospitals Chapel Hill, NC United States. ROR: https://ror.org/0355zfr67 (13) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Citation: Cancer Immunol Res 2026 Jul 15 Epub07/15/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42455126

    Tags:
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