CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1
Cancer Cell, vol. 41, pp. 1817–1828.e9
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.
Authors 37
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German Cancer Research Center · Shanghai Jiao Tong University · Renji Hospital · Shanghai Cancer Institute · State Key Laboratory of Oncogene and Related Genes
Affiliation as printed
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
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
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German Cancer Research Center · Heidelberg University
Affiliation as printed
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
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Memorial Sloan Kettering Cancer Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
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
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Biochemistry, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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German Cancer Research Center · Heidelberg University
Affiliation as printed
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
Faculty of Medicine, Heidelberg University, 69120 Heidelberg, Germany
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Affiliation as printed
Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Stevens Institute of Technology
Affiliation as printed
Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA
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Memorial Sloan Kettering Cancer Center
Affiliation as printed
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Shanghai Jiao Tong University · Tongren Hospital
Affiliation as printed
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111, Xianxia Road, Shanghai 200336, China
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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German Cancer Research Center · Heidelberg University
Affiliation as printed
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
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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German Cancer Research Center · Shanghai Jiao Tong University · Renji Hospital · Shanghai Cancer Institute · State Key Laboratory of Oncogene and Related Genes
Affiliation as printed
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
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
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The Netherlands Cancer Institute
Affiliation as printed
Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · DKFZ-ZMBH Alliance
Affiliation as printed
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
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Adaptive Immunity and Lymphoma , Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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German Cancer Research Center · DKFZ-ZMBH Alliance
Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Molecular Neurogenetics, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division T Cell Metabolism, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Stevens Institute of Technology
Affiliation as printed
Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA
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Agency for Science, Technology and Research · National University of Singapore · Singapore Immunology Network · Netherlands Proteomics Centre
Affiliation as printed
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
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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Affiliation as printed
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
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Shanghai Jiao Tong University · Tongren Hospital · Nanjing Drum Tower Hospital
Affiliation as printed
Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111, Xianxia Road, Shanghai 200336, China
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Memorial Sloan Kettering Cancer Center
Affiliation as printed
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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The Netherlands Cancer Institute
Affiliation as printed
Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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Shanghai Jiao Tong University · Renji Hospital · Shanghai Cancer Institute · State Key Laboratory of Oncogene and Related Genes
Affiliation as printed
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Biochemistry, Netherlands Cancer Institute, Oncode Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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Christian U. Blank Aachen
Leiden University · Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
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
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Ton N. Schumacher Aachen
Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
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
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Affiliation as printed
German Cancer Research Center (DKFZ) Heidelberg, Division Immune Regulation in Cancer, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: c.sun@dkfz.de
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