Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 3, Pages 1036-1049Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-0706
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Funding
- NIH [R21CA137725, R01CA138930, P01CA154778, R01CA173200]
- Hollings Cancer Center Shared Resources at MUSC [P30 CA138313]
- University of Arizona Cancer Center support grant [P30CA023074]
- DOD [W81XWH-12-1-0560]
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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 subcutane-ously 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 ofmemory-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.
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