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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 6

Pharmaceutical expansion of precursor Th17 cells.

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Pharmaceutical expansion of precursor Th17 cells.
(A–C) PI3Kδ inhibition...
(A–C) PI3Kδ inhibition expands precursor Th17 cells with central memory properties. (A and B) Representative FACS plots showing memory phenotype on ICOS-costimulated Th17 cells expanded with distinct inhibitors as indicated (day 7). (C) Expression of central memory markers (CD62L, CCR7, CD28) and an effector memory marker (CCR6) on Th17 cells in the absence (control) or presence of inhibitors. (D and E) CAL-101 decreases FoxP3; Ly294002 supports FoxP3. Representative FACS plots showing FoxP3+CD25hi Tregs in Th17 cells expanded in the presence of distinct inhibitors, before and after secondary stimulation in vitro. (F–H) CAL-101 favors TCM over Tregs in Th17 cultures. (F) Quantification of CD44hiCD62Lhi central memory T (TCM) cells, (G) FoxP3+CD25hi Tregs, and (H) the ratio of TCM cells to Tregs in cultures and expanded with CAL-101 and/or indomethacin (Indo), on day 8 (gated on CD4+, Vβ14+ cells). Data represent mean ± SEM of at least 3 independent experiments. One-way ANOVA followed by Tukey HSD post-hoc test and Student’s t test were applied. *P < 0.05, **P < 0.01, ***P < 0.001. Experiments in Figure 6 were performed concurrently, thus all data can be compared with one another.

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