Investigating the mechanism behind tumor expression of CD58 – a costimulatory ligand on tumors that engages CD2 on T and NK cells, inducing cell adhesion, activation and cytolytic activity – researchers found that CMTM6 on the tumor cell surface directly interacted with CD58 and protected it from degradation. While CMTM6 also supported PD-L1 in a similar fashion, its support for CD58 was dominant, as co-blockade of PD-L1 and CD58 reduced antitumor T cell activation, and CMTM6 and CD58 were critical for the induction of antitumor T cell responses. Higher expression of CMTM6 and CD58 in patient biopsies was associated with favorable responses to ICB.
Contributed by Lauren Hitchings
ABSTRACT: The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.
Author Info: (1) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; State Key Laboratory of Oncogenes and
Author Info: (1) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (2) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. (3) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (5) Division of Biochemistry, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (6) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Medicine, Heidelberg University, 69120 Heidelberg, Germany. (7) Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. (8) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (9) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. (10) Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA. (11) Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (12) Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111, Xianxia Road, Shanghai 200336, China. (13) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (14) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (15) Department of Immunology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (16) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. (17) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (18) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (19) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (20) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (21) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (22) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (23) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. (24) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany. (25) Faculty of Medicine, Heidelberg University, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ) Heidelberg, Division Molecular Neurogenetics, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (26) German Cancer Research Center (DKFZ) Heidelberg, Division Adaptive Immunity and Lymphoma , Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (27) German Cancer Research Center (DKFZ) Heidelberg, Division Molecular Neurogenetics, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (28) German Cancer Research Center (DKFZ) Heidelberg, Division T Cell Metabolism, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. (29) Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA. (30) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Padualaan 8, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(_)STAR), Singapore 138648, Singapore; Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore. (31) Department of Immunology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (32) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Padualaan 8, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands. (33) Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. (34) Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (35) Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (36) State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (37) Division of Biochemistry, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. (38) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Medical Oncology, Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. Electronic address: c.blank@nki.nl. (39) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Hematology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. Electronic address: t.schumacher@nki.nl. (40) German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: c.sun@dkfz.de.
