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Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.

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-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. 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.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC6361669 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.

Chatterjee Shilpak S Chakraborty Paramita P Daenthanasanmak Anusara A Iamsawat Supinya S Andrejeva Gabriela G Luevano Libia A LA Wolf Melissa M Baliga Uday U Krieg Carsten C Beeson Craig C CC Mehrotra Meenal M Hill Elizabeth G EG Rathmell Jeffery C JC Yu Xue-Zhong XZ Kraft Andrew S AS Mehrotra Shikhar S

Clinical cancer research : an official journal of the American Association for Cancer Research 20181016 3

<h4>Purpose</h4>Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of <i>ex vivo</i>-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 import ...[more]

PMID: 30327305

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Project description:BackgroundThe potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed.Methodology/principal findingsBy applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPim, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with E. multilocularis CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells.Conclusions/significanceRepurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.

Dataset Information

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.

Publications

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.

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