Identifying a uniform T cell signature associated with protective anti-tumor immunity and autoimmune systemic sclerosis

Abstract

Abstract Precise tug-of-war between immunosuppressive regulatory T (Treg) cells and inflammatory IL-17-producing (Th17) cells ensures appropriate reactivity to pathogenic challenge. While an imbalance towards Tregs leads to suboptimal responses as observed in cancer, unchecked Th17 activity leads to autoimmunity. Though numerous mechanisms have been identified for how Tregs suppress effector cells, productive effector T cell responses are believed to result from passive escape of Treg suppression. Here we report a novel active role for Th17 cells in dampening Tregs to promote effector activity in the context of melanoma. We hypothesize that Th17 cells can physically impede Treg suppression resulting in enrichment of CD8 T cell prevalence and effector function. Using a melanoma mouse model to characterize Th17 effectors responsible for inhibiting Tregs, we found elimination of IL-17-producing cells prevents vaccine-induced anti-melanoma immune responses. This suggests Th17 cells are important for induction of CD8-mediated anti-tumor immunity. Using RNA-Seq analysis, we generated a gene expression (GE) signature to characterize Th17 effectors responsible for inhibiting Tregs in the context of tumor vaccination. Interestingly, increased ratio of Th17 to Treg cells may contribute to pathogenesis of localized and systemic scleroderma. Diminished Treg- and enhanced Th17-associated genes are consistently found in scleroderma patient skin, leading us to hypothesize that scleroderma pathogenesis has a similar Th17 GE signature to that associated with enhanced tumor clearance. Using the tumor-associated Th17 GE signature to examine scleroderma patient samples we determined transcriptional overlap between the Th17 cell subsets.