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β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity
Kinga Majchrzak, … , Sherine S.L. Chan, Chrystal M. Paulos
Kinga Majchrzak, … , Sherine S.L. Chan, Chrystal M. Paulos
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e90547. https://doi.org/10.1172/jci.insight.90547.
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Research Article Immunology Oncology

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

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Abstract

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while β-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and β-catenin inhibitors. Moreover, these cells regained β-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. This finding shines a light on ways to repurpose FDA-approved drugs to augment T cell–based cancer immunotherapies.

Authors

Kinga Majchrzak, Michelle H. Nelson, Jacob S. Bowers, Stefanie R. Bailey, Megan M. Wyatt, John M. Wrangle, Mark P. Rubinstein, Juan C. Varela, Zihai Li, Richard A. Himes, Sherine S.L. Chan, Chrystal M. Paulos

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Figure 4

β-Catenin and p110δ inhibition augments antitumor Th17 immunity.

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β-Catenin and p110δ inhibition augments antitumor Th17 immunity.
(A and ...
(A and B) Treating ICOS-activated Th17 cells with indomethacin (Indo) plus CAL-101 improves their capacity to regress tumors. (A) Average tumor growth curve. (B) Survival after transfer of 0.75 × 106 TRP-1 CD4+ T cells polarized toward a Th17 phenotype were expanded with TRP-1 peptide and ICOS agonist and/or primed in vitro with CAL-101 or Indo. Percentage survival of mice; n = 6–9 mice/group. Mantel-Cox curves compared by log-rank test; *P < 0.05, ***P < 0.001. (C–E) Pan inhibition of PI3 kinases with Ly294002 does not replace the effectiveness of CAL-101. (C) Average tumor growth curve. (D) Survival after transfer of 0.75 × 106 TRP-1 Th17 cells stimulated with TRP-1 peptide and ICOS agonist and expanded in vitro with Ly294002 and/or Indo. Percentage survival by Mantel-Cox curves, compared by log-rank test; ***P < 0.001. (E) Individual tumor growth curves after transfer of 0.75 × 106 TRP-1 ICOS-activated Th17 cells expanded in vitro with inhibitors, as indicated. Cells were transferred into irradiated (5-Gy total body irradiation) mice bearing established B16F10 melanomas. Tumor growth was measured every 2 to 3 days; n = 9 mice/group. Representative of 2 independent experiments. NT, no treatment.

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