Th159 - TMEM176B Is a Druggable Intrinsic Driver of Protumoral Th17 Lymphocytes

Abstract Text: A potential role for Th17 lymphocytes in tumor immunity remains controversial. Intratumoral Th17 cells have been associated with good but also with bad prognosis in cancer and particularly in anti-PD-1 therapy. The dual role that Th17 cells seem to play in cancer can be explained by the great heterogeneity and/or plasticity of these cells. Developing a pharmacological strategy to modulate Th17 cells polarity is therefore highly relevant for cancer immunotherapy. Here, we unveil the immunoregulatory cation channel TMEM176B as a suppressor of anti-tumoral Th17 responses. Accordingly, inhibition of TMEM176B using BayK8644 triggers Th17 effector responses and reprograms subsets of exhausted CD8+ T cells under PD-1/PD-L1 blockers in two different murine cancer models. Adoptive cell transfer of Th17 cells modulates subsets of exhausted CD8+ T cells and improves the anti-tumor efficacy of PD-1 blockers. Mechanistically, intrinsic expression of TMEM176B drives a regulatory program within Th17 lymphocytes. Pharmacological inhibition of TMEM176B as well as its genetic deletion were associated with an effector phenotype of Th17 cells, increased phosphorylation of AKT, improved metabolic fitness and impaired immune-regulatory capacities in vitro. WT but not Tmem176b-/- Th17 cells were able to undermine terminal CD8+ T cell exhaustion and mitochondrial fitness. In melanoma patients, Th17-related genes were positively correlated with stem-like exhausted CD8+ T cells. At the molecular level, in silico docking studies suggest that BayK8644 blocks critical amino acids required for ion transport by TMEM176B. These findings highlight the potential of TMEM176B inhibitors to modulate Th17 lymphocytes and thus enhance responses to PD-1/PD-L1 blockers.