Targeting PIM kinase with PD1 inhibition improves immunotherapeutic antitumor t-cell response

Shilpak Chatterjee, Paramita Chakraborty, Anusara Daenthanasanmak, Supinya Iamsawat, Gabriela Andrejeva, Libia A. Luevano, Melissa Wolf, Uday Baliga, Carsten Krieg, Craig C. Beeson, Meenal Mehrotra, Elizabeth G. Hill, Jeffery C. Rathmell, Xue Zhong Yu, Andrew S. Kraft, Shikhar Mehrotra

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Purpose: Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor. Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100-reac-tive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both. Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upre-gulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination. Conclusions: This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.

Original languageEnglish (US)
Pages (from-to)1036-1049
Number of pages14
JournalClinical Cancer Research
Volume25
Issue number3
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chatterjee, S., Chakraborty, P., Daenthanasanmak, A., Iamsawat, S., Andrejeva, G., Luevano, L. A., Wolf, M., Baliga, U., Krieg, C., Beeson, C. C., Mehrotra, M., Hill, E. G., Rathmell, J. C., Yu, X. Z., Kraft, A. S., & Mehrotra, S. (2019). Targeting PIM kinase with PD1 inhibition improves immunotherapeutic antitumor t-cell response. Clinical Cancer Research, 25(3), 1036-1049. https://doi.org/10.1158/1078-0432.CCR-18-0706