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β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity
Kinga Majchrzak1,2,3,4, Michelle H Nelson1,3,4, Jacob S Bowers1,3,4
1Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
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.
Insights
Inhibiting specific pathways in T helper 17 (Th17) cells unexpectedly enhanced their anti-tumor capabilities. These modified Th17 cells, when used in cancer immunotherapy, led to durable tumor regression and long-term cures.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Signaling
Background:
- Induction of T helper 17 (Th17) cells via Inducible T-cell costimulator (ICOS) generates durable memory responses against tumors.
- ICOS signaling activates the PI3K/p110δ/Akt and Wnt/β-catenin pathways within Th17 cells.
Purpose of the Study:
- To investigate the impact of coinhibiting PI3Kδ and β-catenin pathways on Th17 cell function and anti-tumor efficacy.
- To explore the potential of repurposing FDA-approved drugs for T cell-based cancer immunotherapies.
Main Methods:
- Th17 cells were generated and treated with inhibitors targeting PI3Kδ and β-catenin pathways.
- The biological fate, gene expression (RORγt, FoxP3, Tcf7), cytokine secretion (IL-17, IL-2), and in vivo anti-tumor activity of treated Th17 cells were assessed.
- Tumor regression and long-term curative responses in mice infused with modified Th17 cells were evaluated.
Main Results:
- Coinhibition of PI3Kδ and β-catenin reduced RORγt expression and IL-17 secretion but unexpectedly enhanced Th17 cell anti-tumor efficacy.
- PI3Kδ inhibition promoted central memory precursor Th17 cells with regulatory properties, while β-catenin inhibition increased Th17 multifunctionality.
- Upon restimulation, treated Th17 cells re-expressed RORγt, IL-17, β-catenin, Tcf7, and Akt, leading to heightened IL-2 production, persistence, and solid tumor eradication without assistance from NK and CD8 T cells.
Conclusions:
- Dual inhibition of PI3Kδ and β-catenin pathways reprograms Th17 cells for potent anti-tumor immunity.
- This strategy offers a novel approach to enhance T cell-based cancer immunotherapies by leveraging existing drug classes.