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PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity
Anusara Daenthanasanmak, … , Andrew S. Kraft, Xue-Zhong Yu
Anusara Daenthanasanmak, … , Andrew S. Kraft, Xue-Zhong Yu
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2787-2801. https://doi.org/10.1172/JCI95407.
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Research Article Immunology Transplantation

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

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Abstract

PIM kinase family members play a crucial role in promoting cell survival and proliferation via phosphorylation of their target substrates. In this study, we investigated the role of the PIM kinases with respect to T cell responses in transplantation and tumor immunity. We found that the PIM-2 isoform negatively regulated T cell responses to alloantigen, in contrast to the PIM-1 and PIM-3 isoforms, which acted as positive regulators. T cells deficient in PIM-2 demonstrated increased T cell differentiation toward Th1 subset, proliferation, and migration to target organs after allogeneic bone marrow transplantation, resulting in dramatically accelerated graft-versus-host disease (GVHD) severity. Restoration of PIM-2 expression markedly attenuated the pathogenicity of PIM-2–deficient T cells to induce GVHD. On the other hand, mice deficient in PIM-2 readily rejected syngeneic tumor, which was primarily dependent on CD8+ T cells. Furthermore, silencing PIM-2 in polyclonal or antigen-specific CD8+ T cells substantially enhanced their antitumor response in adoptive T cell immunotherapy. We conclude that PIM-2 kinase plays a prominent role in suppressing T cell responses, and provide a strong rationale to target PIM-2 for cancer immunotherapy.

Authors

Anusara Daenthanasanmak, Yongxia Wu, Supinya Iamsawat, Hung D. Nguyen, David Bastian, MengMeng Zhang, M. Hanief Sofi, Shilpak Chatterjee, Elizabeth G. Hill, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu

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Figure 7

PIM-2 kinase suppresses antitumor immunity primarily mediated by CD8+ T cells.

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PIM-2 kinase suppresses antitumor immunity primarily mediated by CD8+ T ...
(A) Isotype control antibodies (IgG) or anti-CD8 (2.43) antibody were administered i.p. to PIM-2–/– tumor-bearing mice twice weekly (200 μg/mouse). Depletion of CD8+ T cells was confirmed by flow cytometry before tumor infusion. (B) Survival of tumor-bearing mice treated with antibody was monitored until day 70. WT tumor-bearing mice given IgG and heterozygous PIM-2 mice (PIM-2+/–) with no treatment were used as control groups (n = 6 mice per group). (C) Diagram of adoptive T cell transfer. 2 × 105 TS-1 tumor cells were infused into mice, and tumors were allowed to establish in WT mice for 6 days. Tumor-bearing mice were sublethally irradiated at 500 cGy followed by transfer of 2 × 106 CD8+ T cells isolated from WT and PIM-2–/– mice. Irradiated tumor-bearing mice without T cell transfer were used as controls. (D) Survival of tumor-bearing mice is shown until day 100 (n = 9 mice per group). (E–G) B6 mice were injected i.v. with 5 × 105 B16 tumor cells and tumors that were allowed to establish for 6 days. These tumor-bearing mice were sublethally irradiated and received adoptive transfer of 1 × 106 Pmel-1 cells in which PIM-2 was silenced with LV-shPIM-2. (E) Virus transduction efficiency is illustrated by percentages of GFP+ cells. Transduced Pmel-1 cells were stimulated with PMA and ionomycin and measured for IFN-γ and TNF-α secretion. (F) Tumor growth was monitored with bioluminescent imaging. (G) Survival of tumor-bearing mice is depicted (n = 9–10 mice per group) by log-rank test. *P < 0.05, ***P < 0.001.
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