Description

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

Kinga Majchrzak^1,2, Michelle H. Nelson^1,3, Jacob S. Bowers¹, Stefanie R. Bailey¹, Megan

M. Wyatt^1,2, John M. Wrangle⁴, Juan C. Varela⁴, Mark P. Rubinstein³, Zihai Li¹, Richard A.

Himes⁵, Sherine S. L. Chan⁶ and Chrystal M. Paulos^1,3

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