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Majchrzak K, Nelson MH, Bowers JS, et al. β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity. JCI Insight. 2017;2(8)doi: 10.1172/jci.insight.90547.
Majchrzak, K., Nelson, M. H., Bowers, J. S., Bailey, S. R., Wyatt, M. M., Wrangle, J. M., Rubinstein, M. P., Varela, J. C., Li, Z., Himes, R. A., Chan, S. S., & Paulos, C. M. (2017). β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity. JCI insight, 2(8), . https://doi.org/10.1172/jci.insight.90547
Majchrzak, Kinga, et al. "β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity." JCI insight vol. 2,8 (2017). doi: https://doi.org/10.1172/jci.insight.90547
Majchrzak K, Nelson MH, Bowers JS, Bailey SR, Wyatt MM, Wrangle JM, Rubinstein MP, Varela JC, Li Z, Himes RA, Chan SS, Paulos CM. β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity. JCI Insight. 2017 Apr 20;2(8). doi: 10.1172/jci.insight.90547. eCollection 2017 Apr 20. PMID: 28422756; PMCID: PMC5396523.
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JCI Insight. 2017 Apr 20;2(8). doi: 10.1172/jci.insight.90547. eCollection 2017 Apr 20.

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

JCI insight

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 Sl Chan, Chrystal M Paulos

Affiliations

  1. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
  2. Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
  3. Department of Surgery.
  4. Department of Dermatology and Dermatologic Surgery, and.
  5. Department of Hematology and Oncology, Medical University of South Carolina, Charleston, South Carolina, USA.
  6. Department of Chemistry and Biochemistry, College of Charleston, Charleston, South Carolina, USA.
  7. Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
  8. Neuroene Therapeutics, Mount Pleasant, South Carolina, USA.

PMID: 28422756 PMCID: PMC5396523 DOI: 10.1172/jci.insight.90547

Abstract

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.

Keywords: Immunology; Oncology

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