Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8(+) T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

CD8(+) T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8(+) T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8(+) T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226(neg) CD8(+) T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8(+) tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226(-/-) mice. Anti-CD137 (4-1 BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8(+) T cell function and limits the efficacy of cancer immunotherapy.