학술논문
The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.
Document Type
Academic Journal
Author
Kilian M; 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.; Friedrich MJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Lu KH; 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.; Vonhören D; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Jansky S; Department of Pediatric Hematology and Oncology, Clinic of Pediatrics III, University Hospital Essen, Essen, Germany.; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Michel J; 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.; Keib A; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Stange S; 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.; Hackert N; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Kehl N; 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.; Hahn M; 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.; Habel A; Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.; Jung S; 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.; Jähne K; 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.; Sahm F; 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.; Betge J; 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.; Cerwenka A; 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.; Westermann F; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Dreger P; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Raab MS; 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.; Meindl-Beinker NM; Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.; DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany.; Ebert M; Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.; DKFZ-Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany.; Bunse L; 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.; Müller-Tidow C; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Schmitt M; Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.; Platten M; 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.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101688624 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2470-9468 (Electronic) Linking ISSN: 24709468 NLM ISO Abbreviation: Sci Immunol Subsets: MEDLINE
Subject
Language
English
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.