Kilian, Friedrich, and Lu et al. showed that activated human T cells (primarily CD8+ TEFF cells, but also granzyme A+ CD4+ TEM cells) and CD19-CAR T cells expressed high cell surface levels of and did not shed the checkpoint molecule B7H6, a ligand for NK cell-activating receptor NKp30, to target them for autologous NK cell cytolysis. T cell proliferation, persistence, and CAR T cell antitumor activity were limited by NK cells in humanized, leukemia-bearing mouse models in a B7H6-dependent manner. In a cohort of patients with esophageal cancer, poor ICI response was associated with an increased intratumoral abundance of NK cells as compared to T cells.
Contributed by Paula Hochman
ABSTRACT: Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6(+) T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.
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) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (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. Department of Pediatric Hematology and Oncology, Clinic of Pediatrics III, University Hospital Essen, Essen, Germany. (4) Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (5) Department of Pediatric Hematology and Oncology, Clinic of Pediatrics III, University Hospital Essen, Essen, Germany. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. (6) 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. (7) Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (8) 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. (9) Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (10) 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. (11) 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. (12) Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany. (13) 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. (14) 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. (15) Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany. Clinical Cooperation Unit (CCU) Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. (16) Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. (17) DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany. Department of Immunobiochemistry, Mannheim Institute for Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. (18) Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (19) Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. (20) Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit (CCU) Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (21) Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany. (22) Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany. (23) 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. (24) Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (25) Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany. (26) 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. DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany. Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany. Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
