?-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