Reduced ectonucleotidase expression on TGF-β independent Th17 improves tumor control (VAC11P.1006)

Abstract

Abstract Amongst various effector CD4+ T cells, T helper (Th)-17 subsets hold promise in adoptive T cell transfer therapy for cancer. However, ex vivo programming of Th17 cells in presence of TGF-β increases cell surface expression of ectonucleotidases CD39 and CD73, that in turn increases susceptibility to immunosuppression and reduced effector phenotype. Our data shows that ATP mediated suppression of IFN-γ production by Th17 cells can be overcome either by genetic ablation of CD73 or generating TGF-β independent Th17 in presence of IL-1β. An in vivo comparison of anti-tumor potential between TGF-β dependent and independent Th17 showed that Th17 cells generated in presence of IL-1β are more efficacious than TGF-β dependent Th17 cells in controlling B16 melanoma. IL-1β dependent Th17 cells are also highly polyfunctional and express high level of pathogenic genes, such as T-bet and granzyme B that results in increased cytotoxic potential. It is likely that effector property of IL-1β dependent Th17 is due to their high glycolytic capacity, since generating IL-1β dependent Th17 cells in pyruvate containing media impaired glycolysis and its anti-tumor potential. Thus, our data suggests that owing to TGF-β induced ectonucleotidase expression, ex vivo culture conditions for generating Th17 cells need to be reconsidered in favour of TGF-β independence for exploiting their full potential in adoptive T cell therapy.