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 they 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.

High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy

“…Indeed, we also found an up-regulation of CD11a in the CD8 + T cell compartment of responder patients, which has been shown to be essential for migration to lymph nodes and distal sites 38,42 . Lastly, Th17 cells were recently demonstrated to be potent apoptosis-resistant anti-tumor effector cells 43,44 .…”

Pivotal factors associated with the immunosuppressive tumor microenvironment and melanoma metastasis

“…Our study revealed that IL2RA、IL2RG, IFNG, and IL7R were hub genes in melanoma metastasis and involved in JAK-STAT signaling pathway that was identified as an central signaling pathway in metastatic melanoma, which was rarely illustrated in previous studies. [22][23][24][25] Comparable results are observed with Non-Hodgkin's lymphoma, in which activation of IL2Rγ-JAK3-STAT5 signaling pathway significantly promotes cancer progression while knockdown of IL2Rγ garners the same effect as Tofacitinib, a JAK inhibitor that effectively inhibits the activity of JAK1 and JAK3. 26,27 Actually, Julianna Volkó et al found the assembly of IL2R may occur and exert its function in the cytoplasm, which is a probable factor in immunotherapy resistance, 28 as IL2Rβ and IL2Rγ could form ligand-independent homodimerization and stimulate mutant JAK3-STAT pathway.…”

Identification of Age-Associated Transcriptomic Changes Linked to Immunotherapy Response in Primary Melanoma

“…Therapeutic benefit from immunotherapy was observed in patients with the PD-L1-negative tumors; however, resistance to immunotherapy remains a challenge [ 33 , 34 ]. Indeed, gene set enrichment analysis (GSEA) of transcriptomic data confirmed the significant enrichment of genes in the T cell receptor signaling, PD-L1 expression and PD-1 checkpoint and JAK-STAT signaling pathways, which are essential pathways in melanoma ( Figure 4 D–G) [ 35 , 36 , 37 ].…”