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

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

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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.

Original languageEnglish (US)
Pages (from-to)2787-2801
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number7
DOIs
Publication statusPublished - Jul 2 2018

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ASJC Scopus subject areas

  • Medicine(all)

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Daenthanasanmak, A., Wu, Y., Iamsawat, S., Nguyen, H. D., Bastian, D., Zhang, M. M., ... Yu, X. Z. (2018). PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity. Journal of Clinical Investigation, 128(7), 2787-2801. https://doi.org/10.1172/JCI95407