Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity
Kinga Majchrzak, … , Sherine S.L. Chan, Chrystal M. Paulos
Kinga Majchrzak, … , Sherine S.L. Chan, Chrystal M. Paulos
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e90547. https://doi.org/10.1172/jci.insight.90547.
View: Text | PDF
Research Article Immunology Oncology

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

  • Text
  • PDF
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.

Authors

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

×

Figure 2

ICOS stimulation induces β-catenin and PI3K/Akt/p110δ in Th17 cells.

Options: View larger image (or click on image) Download as PowerPoint
ICOS stimulation induces β-catenin and PI3K/Akt/p110δ in Th17 cells.
(A)...
(A) ICOS confers a distinct gene expression profile in Th17 cells. Relative expression of Th17-associated and stemness genes RORC, IL17A, cMAF, IL21, CPT1a, Tcf7, and Lef1 in TRP-1 Th17 cells stimulated with ICOS or CD28, assayed via qPCR. Analysis performed on listed transcripts relative to β-actin, compared by Student’s t test; *P < 0.05, **P < 0.01, ***P < 0.001. (B) ICOS induces RORγt in Th17 cells to a greater extent than CD28 signaling. Representative histogram of RORγt in TRP-1 Th17 cells stimulated with an ICOS (solid line) or CD28 (dashed line) agonist (day 8). (C) ICOS induces β-catenin and P13K/Akt in Th17 cells. Western blot analysis of β-catenin and phosphoAkt (serine 473) expression in day 8–expanded Th17 cells. (D and E) ICOS–/–Th17 cells express low levels of β-catenin and p110δ/Akt proteins compared with WT Th17 cells. (D) Western blot analysis of nuclear (top) and cytoplasmic (bottom) β-catenin expression in WT versus ICOS–/–Th17 cells stimulated with an ICOS or CD28 agonist (day 8). (E) Western blot analysis of cytoplasmic PI3K-p110δ (top) and phosphoAkt (serine 473) (bottom) in WT TRP-1 Th17 cells (stimulated with an ICOS or CD28 agonist. Representative of 2 or 3 separate experiments.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts