RNA binding protein PCBP1 is an intracellular immune checkpoint for shaping T cell responses in cancer immunity

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (T-eff) cells into regulatory T (T-reg) cells, by restricting the expression of T-eff cell-intrinsic T-reg commitment programs. This was critical for stabilizing T-eff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored T-reg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining T-eff cell functions in cancer immunity.