Pharmaceutical co-inhibition of β-catenin and p110δ paradoxically expands stem memory Th17 cells with heightened antitumor activity

Identification: 4046


Description

Pharmaceutical co-inhibition of β-catenin and p110δ paradoxically expands stem memory Th17 cells with heightened antitumor activity

Kinga Majchrzak1,2, Michelle H. Nelson1,3, Jacob S. Bowers1, Stefanie R. Bailey1, Megan

M. Wyatt1,2, John M. Wrangle4, Juan C. Varela4, Mark P. Rubinstein3, Zihai Li1, Richard A.

Himes5, Sherine S. L. Chan6 and Chrystal M. Paulos1,3

1Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA

2Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159, 02-776 Warsaw, Poland

3Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

4Department of Hematology and Oncology, Medical University of South Carolina, Charleston, SC, 29425, USA

5Department of Chemistry, College of Charleston, Charleston, SC, 29424, USA

6Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA

ICOS co-stimulation generates Th17 cells with durable memory responses to tumor. We found herein that ICOS signaling induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Co-inhibiting p110δ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, in turn reducing their ability to secrete IL-17A. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when transferred into mice, leading to long-term cures. PI3K/p110δ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties and heightened stemness; while β-catenin inhibition enhanced Th17 pluripotency in vivo. Our data reveal that Th17 cells possess enhanced stemness and mediate robust antitumor immunity when treated with FDA-approved drugs that inhibit p110δ and β-catenin.

CMP Funding for this project: NCI R01 CA175061

Credits

Credits: None available.

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