Tumor CD155 Drives Resistance to Immunotherapy by Downregulating the Activating Receptor CD226 in CD8 + T Cells

The upregulation of inhibitory molecules is a major driver of immune escape in cancer. In contrast, less is known about the regulation of T cell activating receptors within the tumor microenvironment. Here, we describe that tumor derived CD155, a transmembrane glycoprotein of the immunoglobulin superfamily, downregulates the activating receptor CD226 (DNAM-1) in mouse and human CD8+ T cells, leading to profound loss of effector function and cancer immune evasion. Mechanistically, CD155 drives internalisation of CD226 through phosphorylation of tyrosine 319 (CD226Y319). Accordingly, in T cells a mutation in Y319 led to increased CD226 surface expression improving the efficacy of cancer immunotherapies in mouse models of cancer. In pre-treatment samples from melanoma patients, CD226+ CD8+ T cells significantly correlated with response to immunotherapy and survival. In summary, we discovered a new paradigm in which tumor cells escape destruction by T cells through targeted downregulation of an activating receptor.