Eomes-Dependent CD226 Loss Alters TCR Responsiveness and Restrains CD8+ T Lymphocyte Anti-Tumor Functions

Abstract

Although anti-PD-1 and anti-CTLA-4 based immune checkpoint blockade (ICB) has represented a turning point in cancer care, clinical responses are observed only in a fraction of cancer patients. Most research focuses on the identification of additional inhibitory receptors restraining the anti-tumor functions of CD8+ T cells. By contrast, herein, we found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. Using cancer patients’ samples and preclinical mouse models, we discovered that dysfunctional CD226-negative CD8+ T cells progressively accumulated in the tumor microenvironment through a mechanism involving the T-box transcription factor Eomesodermin (EOMES). More importantly, we demonstrated that CD226-negative tumor infiltrating lymphocytes had reduced anti-tumor functions and failed to respond to ICB. Altogether, our results revealed that CD226 loss is a critical immune escape mechanism restraining CD8+ T cell function and potentially affecting the therapeutic efficacy of cancer immunotherapy.