CPI-444 is a potent, oral, selective A2AR antagonist. CD8 T cell depletion abrogates the efficacy of CPI-444 treatment as a single agent as well as in combination with anti-PD-L1, demonstrating a role for CD8 T cells in mediating primary and secondary immune responses. Anti-tumor efficacy of CPI-444±anti-PD-L1 is associated with increased CD8+ cell infiltration and activation in MC38 tumor tissues, and a corresponding rise in PD-1 expression on CD8 T cells in the spleen. Additionally, levels of immune checkpoints are modulated by treatment with CPI-444, including GITR, OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting a broad role for adenosine mediated immunosuppression.