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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 3

β-Catenin and PI3Kδ inhibition alters the cytokine and transcription factor profile in ICOS-activated Th17 cells.

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β-Catenin and PI3Kδ inhibition alters the cytokine and transcription fac...
(A and B) PI3Kδ but not β-catenin inhibition suppresses IL-17A and IFN-γ secretion by ICOS-activated Th17 cells. (A) Representative FACS plot of cytokine production (IL-17A, IFN-γ, IL-2, TNF-α, IL-22) by TRP-1 CD4+ cells polarized toward a Th17 phenotype, costimulated with ICOS agonist for 8 days (vehicle) and expanded in the presence of specific PI3Kδ subunit inhibitor (CAL-101, 10 μM) and/or specific β-catenin inhibitor (indomethacin [Indo], 60 μM). (B) Cytokine production (IL-17A, IFN-γ, IL-2, TNF-α, IL-22). (C) Blockade of both pathways slightly impairs Th17 cell expansion. Absolute number (×106) of TRP-1 Th17 cells in the absence (vehicle) or presence of CAL-101 and/or Indo, on day 7. Values represent of at least 3 independent experiments. Data in B and C were compared by Student’s t test; *P < 0.05, **P < 0.01, ***P < 0.001. (D and E) Inhibition of p110δ by CAL-101 decreases RORγt, cMaf, and STAT3 expression induced in ICOS-activated Th17 cells. (D) Representative histograms showing expression of transcription factors (RORγt, cMaf, STAT3), and (E) Western Blot analysis of nuclear RORγt and STAT3 expression in TRP-1 Th17 cells in the absence (control) or presence of inhibitors, as indicated (day 8).

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