Targeting PIM2 improves antitumor immunity through promoting effector function and persistence of CD8 T cells. J Clin Invest 2026 Mar 16;136(6)
Date
01/27/2026Pubmed ID
41592107Pubmed Central ID
PMC12987625DOI
10.1172/JCI192928Scopus ID
2-s2.0-105033859897 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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.
Author List
Wu Y, Tian L, Pugel A, Alimohammadi R, Cheng Q, Cui W, Nishimura MI, Ball LE, Lin CW, Mehrotra S, Kraft AS, Yu XZAuthors
Reza Alimohammadi Postdoctoral Researcher 3 in the Obstetrics and Gynecology department at Medical College of WisconsinChien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Enhancer of Zeste Homolog 2 Protein
Female
Humans
Mice
Mice, Knockout
Neoplasm Proteins
Neoplasms, Experimental
Proto-Oncogene Proteins
