Targeting PIM2 improves antitumor immunity through promoting effector function and persistence of CD8 T cells
Yongxia Wu, Linlu Tian, Allison Pugel, Reza Alimohammadi, Qiao Cheng, Weiguo Cui, Michael I. Nishimura, Lauren E. Ball, Chien-Wei Lin, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu
Yongxia Wu, Linlu Tian, Allison Pugel, Reza Alimohammadi, Qiao Cheng, Weiguo Cui, Michael I. Nishimura, Lauren E. Ball, Chien-Wei Lin, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu
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Research Article Cell biology Immunology

Targeting PIM2 improves antitumor immunity through promoting effector function and persistence of CD8 T cells

Abstract

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.

Authors

Yongxia Wu, Linlu Tian, Allison Pugel, Reza Alimohammadi, Qiao Cheng, Weiguo Cui, Michael I. Nishimura, Lauren E. Ball, Chien-Wei Lin, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu

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Figure 7

PIM2 negatively regulates VPRBP/EZH2 activity.

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PIM2 negatively regulates VPRBP/EZH2 activity. (A–C) Splenocytes from WT...
(A–C) Splenocytes from WT or Pim2-KO Pmel mice were activated with 500 ng/mL gp100 peptide for 3 days and subjected to tandem mass tag–based phosphoproteomics analysis with WT n = 5 and KO n = 5. (A) Differential expression analysis for each phosphosite between WT and KO was conducted, and differentially expressed phosphoproteins reported to regulate T cell response are displayed. (B) A pathway analysis was performed in the differentially phosphorylated proteins. The average abundance of the phosphorylated proteins is shown in each pathway. (C) All differentially expressed phosphoproteins are shown in a volcano plot. (D) WT or Pim2-KO CD8 T cells were stimulated with anti-CD3/CD28 for 24 hours. Anti-PIM2 mAb or control IgG was used to pull down PIM2, followed by Western blot detection of EZH2 and VPRBP. The target bands are marked with asterisks. (E) Western blot detection of VPRBP was performed in activated WT or Pim2-KO Pmel cells at 3 days after gp100 stimulation. (F) EZH2 and H3K27Me3 were detected in CD8 T cells after anti-CD3/CD28 stimulation. (G) Pmel splenocytes were activated with gp100 peptide plus 5 ng/mL IL-15 with or without 5 μM GSK126 for 5 days. Frequencies of IL-2+, IFN-γ+, and CD44+CD62L+ (Tcm) are shown. Data represent 2 independent experiments (D–G). Data were analyzed unpaired 2-tailed Student’s t test (A and G). Data are shown as mean ± SEM. *P < 0.05.