By analyzing patient melanomas biopsied before or on ICB, and patient-derived melanoma cells and autologous ex vivo-expanded TILs in co-cultures and in a humanized mouse model, Ho, Melms and Rogava et al. showed that cancer cell CD58 was required for specific T cell-mediated antitumor activity. Cancer cell CD58 loss reduced intratumoral T cell infiltration, expansion, and differentiation, upregulated PD-L1, and boosted immune evasion. CD58 stability and PD-L1 upregulation upon CD58 loss were co-regulated by their competition for CMTM6 binding, which stabilized cell surface proteins via endosomal recycling and reduced lysosomal degradation.
Contributed by Paula Hochman
ABSTRACT: The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
Author Info: (1) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine,
Author Info: (1) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (2) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (3) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (4) Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Klarman Cell Observatory, the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (5) Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium. (6) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (7) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (10) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (11) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA. (12) Proteomics and Macromolecular Crystallography Shared Resource, Columbia University, New York, NY 10032, USA. (13) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (14) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY 10032, USA. (15) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY 10032, USA. (16) Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Immunology, Mayo Clinic, Scottsdale, AZ 85259, USA. (17) Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (18) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA. (19) Department of Pediatrics, Columbia University, New York, NY 10032, USA. (20) Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Division of Rheumatology, Columbia University, New York, NY 10032, USA. (21) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (22) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (23) Department of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA. (24) Department of Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA. (25) Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA; Department of Surgery, Columbia University, New York, NY 10032, USA. (26) Department of Pediatrics, Columbia University, New York, NY 10032, USA. (27) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (28) Department of Dermatology, University Hospital Essen and German Cancer Consortium, Partner Site, 45147 Essen, Germany. (29) Department of Oncology, KU Leuven, 3000 Leuven, Belgium. (30) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA. (31) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (32) Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Department of Oncology, KU Leuven, 3000 Leuven, Belgium. (33) Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, NY 10032, USA; Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Electronic address: bi2175@cumc.columbia.edu.
