PD-1 immune checkpoint blockade can synergize with PSGL-1 inhibition to reinvigorate exhausted T cells

Abstract P-selectin glycoprotein ligand-1 (PSGL-1) is an immune checkpoint regulator that is highly expressed on T cells. PSGL-1- deficient mice infected with chronic lymphocytic choriomeningitis virus (LCMV) were shown to control chronic viral infection due to increased effector function by anti-viral T cells. However, the cell-intrinsic role of PSGL-1 expression on CD4 +and CD8 +T cell exhaustion is not fully known. Using adoptive transfers of WT or PSGL-1-deficient TCR transgenic CD4 +and CD8 +T cells in mice infected with chronic LCMV, we characterized the differentiation and effector response. We found increased expansion and effector function by PSGL-1-deficient T cells early during infection, however, at later stages of infection, PSGL-1-deficient T cells were functionally exhausted. We found that exhausted CD4 +and CD8 +PSGL-1-deficient T cells were reinvigorated more effectively than WT cells after PD-L1 blockade due to their increased proliferation, cytokine production, and accumulation. We also observed increased responses of CD8 +PSGL-1-deficient T cells in melanoma tumors. Our findings showed that PSGL-1 expression was required for the maintenance of both CD8 +and CD4 +exhausted T cells and that PSGL-1 deletion synergized with PD-1 blockade to reinvigorate these cells. These findings highlight an important cell-intrinsic role for PSGL-1 expression in the maintenance and reinvigoration of exhausted T cells. T32 AI 141346 R01 AI13723