Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

Abstract

Adoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8+ T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

• Authors: Daniel J Neitzke, Jacob S Bowers, Kristina Andrijauskaite, Nathaniel S O'Connell, Elizabeth Garrett-Mayer, John Wrangle, Zihai Li, Chrystal M Paulos, David J Cole, Mark P Rubinstein
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 66 Issue 6 Pg. 737-751 (Jun 2017) ISSN: 1432-0851 [Electronic] Germany
• PMID: 28280853 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Interleukin Receptor Common gamma Subunit
• Interleukin-15
• Interleukin-2
• Interleukin-7

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CD4-Positive T-Lymphocytes (immunology)
• Cell Proliferation (drug effects)
• Gene Expression Regulation (drug effects)
• Immunotherapy, Adoptive
• Interleukin Receptor Common gamma Subunit (immunology, metabolism)
• Interleukin-15 (pharmacology)
• Interleukin-2 (pharmacology)
• Interleukin-7 (pharmacology)
• Melanoma, Experimental (immunology, pathology, prevention & control)
• Mice
• Th17 Cells (immunology, metabolism)