Targeting Pim2 improves effector function and longevity of T cells in cancer immunotherapy through regulating autophagy

Abstract

Abstract The Pim kinase family is critically involved in tumorigenesis, yet its role in primary T cells is not well known. We reported that Pim2, distinct from the other two isoforms, inhibits T-cell responses to alloantigen. To study how Pim2 impacts T-cell immunity against cancer, we used murine models of adoptive cell therapy (ACT) and hematopoietic cell transplantation. Pim2 deficiency enhanced the ability of antigen specific CD8 T cells and polyclonal T cells in controlling solid tumor and leukemia growth, respectively. Pim2 deficiency increased cytokine production and metabolic activities of CD8 T cells in vitro and promoted effector but constrained exhausted CD8 subsets in tumor. Pim2-/- CD8 T cells had increased Tcf1 expression and longevity after ACT. Mechanistically, Pim2 binds P62 and constrains T-cell activation through facilitating autophagy. Pim2 deficiency in T cells attenuated LC3 lipidation, P62 degradation as well as autophagosome formation. Augmentation of autophagy via Atg5 overexpression or metformin treatment reduced effector differentiation and anti-tumor function of Pim2-/- T cells. Importantly, a Pim2-specific inhibitor improved murine T-cell immunity against melanoma and leukemia and increased activity of human melanoma-specific T cells and CD19 CAR-T cells. Taken together, Pim2 restrains T-cell anti-tumor immunity through regulating autophagy, and blocking Pim2 enhances effector differentiation and persistence of T cells after cancer immunotherapy.