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?-catenin and PI3K? inhibition expands precursor Th17 cells with heightened stemness and antitumor activity.

ABSTRACT: ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110?/Akt and Wnt/?-catenin pathways in Th17 cells. Coinhibiting PI3K? and ?-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less ROR?t, 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. PI3K? inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while ?-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, ROR?t and IL-17 rebounded in Th17 cells treated with PI3K? and ?-catenin inhibitors. Moreover, these cells regained ?-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.

SUBMITTER: Majchrzak K

PROVIDER: S-EPMC5396523 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Majchrzak Kinga K Nelson Michelle H MH Bowers Jacob S JS Bailey Stefanie R SR Wyatt Megan M MM Wrangle John M JM Rubinstein Mark P MP Varela Juan C JC Li Zihai Z Himes Richard A RA Chan Sherine Sl SS Paulos Chrystal M CM

JCI insight 20170420 8

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 ...[more]

PMID: 28422756

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Project description:Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69- T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.

Dataset Information

?-catenin and PI3K? inhibition expands precursor Th17 cells with heightened stemness and antitumor activity.

Publications

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

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