Targeting PIM Kinase with PD1 inhibition Improves Immunotherapeutic Anti-Tumor T Cell Response

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 anti-tumor response following ACT is hampered either by loss of effector function or survival of the anti-tumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the anti-tumor 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 studies either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacological inhibition (pan-PIM kinase inhibitor, PimKi). Subcutaneous murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100 reactive 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 upregulated expression of memory-associated genes that inversely correlate with glycolysis. Additionally, 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 anti-tumor 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. Conclusion: The present study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhhibition of signaling kinase with check-point inhibition could improve tumor control.

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