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.
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
Illustration of how β-catenin and PI3Kδ coinhibition augments the antitumor activity and durable memory of Th17 cells.
ICOS-activated Th17 cells expanded in the presence of CAL-101 and indomethacin (Indo) possess a central memory phenotype (i.e., elevated CD62L expression). There are fewer regulatory properties (decreased FoxP3 expression) in this culture. Moreover, upon antigen recall in vivo dual-inhibited Th17 cells are multipotent (producing many cytokines) and exhibit elevated nuclear β-catenin and Tcf7 and augmented persistence in the host. These cells possess self-renewal and durable memory responses to solid tumors, enabling them to directly lyse established malignancies without help from endogenous immune cells. This finding shines light on new ways to repurpose FDA-approved drugs to augment cancer immunotherapy.