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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 5

Dual-inhibited Th17 cells directly regress tumor and do not require host NK or CD8 T cells.

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Dual-inhibited Th17 cells directly regress tumor and do not require host...
(A–C) ICOS-activated Th17 cells cultured with indomethacin (Indo) plus CAL-101 engraft to a greater extent than cells subjected to other treatments in the spleen. (A) Percentage and (B) number (×104) of TRP-1 Vβ14+CD45.2+ Th17 cells in the spleens of CD45.1+ recipient mice 6 days after transfer. (C) Donor Vβ14+CD45.2+ Th17 cells secrete IL-17A, IFN-γ, and IL-2 64 days after transfer in CD45.1+ recipient mice when primed with Indo or Indo plus CAL-101. Cytokine production in vivo of Th17 cells expanded in vitro with inhibitors, as indicated. Donor Vβ14+CD45.2+ cells were flow sorted from the spleens of CD45.1+ recipient mice and restimulated with PMA/ionomycin. Data represent mean ± SEM. Student’s t test; *P < 0.05; **P < 0.01; ***P < 0.001. (D) NK cell frequency in the tumors of mice infused with various Th17 treatments. (E–H) Depletion of host NK or CD8 T cells in mice does not abrogate therapy. Individual tumor growth curves of mice treated with 0.75 × 106 transferred TRP-1 Th17 cells expanded with TRP-1 peptide and ICOS agonist and primed in vitro with CAL-101 and Indo. Cells transferred into 5-Gy TBI mice bearing B16F10 melanomas. Mice were antibody depleted of host CD8 or NK cells (100 μg/mouse) twice weekly for the entire experiment, starting 2 days prior to ACT. As a control, mice given Th17 therapy were administered with an IgG isotype. (J) Depletion of donor cells in mice rechallenged with tumor impairs ACT. Surviving mice in (F–H) were rechallenged with B16F10 and then antibody depleted of host CD4 cells (100 μg/mouse) or with (I) an IgG control twice weekly for the first 2 weeks after rechallenge. Percentage survival; n = 13 mice/group. Mantel-Cox curves compared by log-rank test; *P < 0.05. As a control (K and L), naive mice were treated with an IgG isotype control (top right) or treated with a CD4-depleting antibody. Indo + CAL-101 + CD4 depletion is significant different that Indo + CAL-101 + IgG depletion (P < 0.05).

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