Abstract 1412: Immune and metabolic control of Th17 cells by TMEM176B: Potential implication in cancer immunotherapy

Abstract Helper CD4+ T cells are key players in the adaptive immune response that differentiate into different subpopulations. One of these subpopulations are T helper 17 (Th17) cells. In cancer, the role of Th17 cells is still controversial. The dual effect that Th17 cells seem to have in cancer can be explained by the great heterogeneity and/or plasticity of these cells. Two different subpopulations of Th17 cells have been reported: regulatory or “non-pathogenic” Th17 cells and effector or “pathogenic” Th17 cells. We currently know that this dual behavior depends on the cytokine microenvironment in which Th17 cells differentiate. However, the molecular basis of how, when, and why Th17 cells differentiate into effector or regulatory populations, as well as its in vivo relevance, are still poorly understood. Here we show that intrinsic expression of TMEM176B can determine the fate of Th17 cells. TMEM176b is a druggable immunoregulatory ion channel which function was first described by our team. We have found that in in vitro differentiated Th17 cells, Tmem176b is over-expressed in regulatory Th17 cells compared to effector Th17 cells, in agreement with its immunoregulatory properties. Furthermore, we found that Tmem176b influence Th17 polarity, since Th17 in vitro differentiation with IL-6+TGF-β from naïve Tmem176b−/− CD4+ T cells results in an enhanced IFN-γ production. Same results were obtained by pharmacological inhibition of TMEM176B in WT CD4+ T cells. Functional evaluation of these cells showed a decreased regulatory capacity compared to WT Th17 cells. Thus, WT Th17 cells inhibited CD8+ T cell proliferation whereas Tmem176b−/− Th17 cells showed poor inhibitory capacity. Supporting this effector-like phenotype, Tmem176b−/− Th17 cells have higher basal pAKT/AKT ratio compared to WT Th17 cells. Furthermore, Tmem176b−/− Th17 cells have a better metabolic fitness than WT Th17 cells, with higher glycolysis and oxidative phosphorylation. It was reported that the effector role of Th17 cells is dependent on the IL-1β production through ASC-NLRP3-caspase 8 activation. Here we show that Tmem176b−/− Th17 cells stimulated with ATP have a higher Caspase-8 activation compared to WT Th17 cells. All these results suggest that Tmem176b deficiency leads to an effector-like Th17 cell phenotype when cells are differentiated in a regulatory cytokine microenvironment. Moreover, co-culture of Tmem176b−/− Th17 cells with in vitro generated exhausted CD8+ T cells results in a reduction of the frequency of terminal exhausted CD8+ T cells and of mitochondrial reactive oxygen species production compared to co-culture with WT Th17 cells. Therefore, Tmem176b−/− Th17 may have enhanced anti-tumor properties compared to WT Th17 cells. In conclusion, we have identified a new intrinsic regulator of Th17 cells, TMEM176B, which may constitute a molecular target to pharmacologically modulate these cells. Citation Format: Sofia Russo, Mateo Malcuori, Mercedes Segovia, Marcelo Hill. Immune and metabolic control of Th17 cells by TMEM176B: Potential implication in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1412.