Braun et al. found heterogeneous expression of the T cell activation marker CD226 on CD8+ T cells in mouse and human tumors. CD226 expression indicated T cell functionality (activation, cytokine expression, proliferation, cytotoxicity, and immune synapse formation). Upon interaction with its ligand CD155, expressed on tumor cells, CD226 was internalized and degraded, dependent on phosphorylation and CBL-B ubiquitination. CD226 expression improved outcomes of adoptive T cell transfer in mice. Pre-treatment tumor-infiltrating CD226hi T cells correlated with progression-free survival in melanoma patients treated with checkpoint blockade.
Contributed by Alex Najibi
ABSTRACT: The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8 + TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226 hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226 +CD8 + T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
Author Info: (1) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (2) Oncology and Cellular Immunology Laboratory, QIMR Berghofe
Author Info: (1) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (2) Oncology and Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (3) Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (4) The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia (5) Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montreal, Montreal, QC, Canada (7) Department of Medicine, McGill University, Montreal, QC, Canada (8) Department of Medicine, University of Montreal, Montreal, QC, Canada (9) Gordon and Jessie Gilmour Leukemia Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (10) Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany (11) Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia (12) Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (13) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA (14) Institute of Structural Biology, University Hospital Bonn, University of Bonn, Bonn, Germany (15) Institute of Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany (16) Pathology Queensland, Royal Brisbane and Women’s Hospital, University of Queensland Herston, Herston, QLD, Australia (17) Royal Brisbane and Women’s Hospital, University of Queensland Herston, Herston, QLD, Australia (18) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia (19) The University of Sydney, Central Clinical School, Sydney, NSW, Australia (20) Royal North Shore Hospital, Sydney, NSW, Australia (21) Mater Hospital, Sydney, NSW, Australia (22) Royal Prince Alfred Hospital, Sydney, NSW, Australia (23) Department of Dermatology and Allergy, University Hospital Bonn, University of Bonn, Bonn, Germany (24) Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany (25) Institute of Immunobiology, Kantonsspital St.Gallen, St.Gallen, Switzerland (26) Department of Dermatology, Kantonsspital St.Gallen, St.Gallen, Switzerland (27) Institut National de la Sante et de la Recherche Medicale (INSERM) UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse F-31000, France
