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

Abstract The Provirus Integration sites for Moloney murine leukemia virus (Pim) kinase family has been studied extensively in tumorigenesis. We previously reported a key role of Pim2 in negatively regulating T-cell responses to alloantigen. We further investigated how Pim2 regulates T-cell mediated anti-tumor responses using murine models of adoptive cell therapy (ACT) and autologous hematopoietic cell transplantation (HCT). We found that Pim2 −/−Pmel CD8 T cells showed enhanced ability for controlling B16 melanoma growth following ACT. Pim2 −/−T cells were more potent to control C1498 leukemia growth after syngeneic HCT. Mechanistically, Pim2 −/−CD8 T cells exhibited increased effector cytokine production, metabolic activities, and unexpectedly CD62L expression than WT controls following activation. Activated Pim2 −/−CD8 T cells had less apoptosis and exhaustion during expansion in IL-2. In vivo, Pim2 −/−CD8 T cells differentiated more into effector, but less into exhausted or suppressive subsets in tumors. On the other hand, Pim2 −/−CD8 T cells exhibited increased longevity in spleen and tumor draining lymph nodes. Our data indicates that Pim2 negatively regulates CD8 T-cell anti-tumor activity by controlling their persistence in secondary lymphoid organs and effector function in tumors. Blocking Pim2 with a Pim2-specific inhibitor improved graft-versus-leukemia activity after autologous HCT and enhanced anti-melanoma effects after ACT. Pim2 inhibition also increased anti-tumor activity of human melanoma-specific T cells and CD19 CAR-T cells. Taken together, targeting Pim2 may serve as a novel strategy for improving cancer immunotherapy through enhancing differentiation and persistence of effector T cells. NIH R01 CA258440 and R21 CA263140 to Xue-Zhong Yu, MCW Center for Immunology Pilot Award to Yongxia Wu