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.