Kilian and Sheinin et al. demonstrated that MHC-II-restricted antigen presentation on intratumoral blood-borne myeloid (bbm) cells drives cytotoxicity of tumor-reactive CD8+ T cells and response to ICB. Loss of myeloid MHC-II expression led to osteopontin (OPN)-mediated chronic NFAT2 signaling and TOX upregulation, which induced CD8+ T cell dysfunction. Mechanistically, intratumoral MHC class II presentation mediated CD4+ T cell activation, which restricted OPN expression by bbm through IFNγ. In human glioblastoma, reduced MHC-II expression on bbm correlated with increased OPN expression and exhausted intratumoral CD8+ T cell states.
Contributed by Shishir Pant
ABSTRACT: Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8(+) T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4(+) T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8(+) T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.
Author Info: (1) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medic
Author Info: (1) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. (2) Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Blavatnik School of Computer Science, Tel Aviv University, 69978 Tel Aviv, Israel. (3) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (4) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (5) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (7) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (8) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany; Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany. (9) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (10) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (11) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (13) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (14) Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany. (15) Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (16) Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany. (17) DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany; Department of Neuropathology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (18) Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany; DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany. (19) Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: asafmadi@tauex.tau.ac.il. (20) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: l.bunse@dkfz.de. (21) DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany; Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany. Electronic address: m.platten@dkfz.de.
