CELL INTELLIGENCE · 肿瘤细胞治疗研究

The PIM kinase family is critically involved in tumorigenesis, yet its role in primary T cells is understudied. We reported that PIM2, distinct from the other 2 isoforms, inhibits T cell responses to alloantigen. Here, we further established PIM2 as a key negative regulator in antitumor immunity. Pim2 deficiency in tumor antigen-specific or polyclonal T cells enhanced their ability to control tumor growth in murine breast cancer, melanoma, and leukemia models. Pim2 deficiency enhanced cytokine production and metabolic activities in tumor-infiltrating CD8 T cells. Pim2 deficiency increased TCF1 expression and memory-like phenotype in CD8 T cells from lymphoid organs. Mechanistically, PIM2 facilitated LC3 lipidation, P62 degradation, and autophagic flux in T cells, leading to impaired glycolysis and effector cytokine production. Furthermore, through modulating VPRBP kinase phosphorylation, PIM2 inhibited histone methyltransferase activity of EZH2 in CD8 T cells, causing disrupted memory-like phenotype. Notably, the PIM2 inhibitor JP11646 markedly enhanced antitumor T cell response. The immunosuppressive role of PIM2 was validated in human T cells, where inhibition of PIM2 enhanced antitumor responses in engineered human T cells, including melanoma-specific TCR T cells and CD19 CAR T cells. Collectively, PIM2 represents a promising target for improving cancer immunotherapy through enhancing effector differentiation and persistence of CD8 T cells.