Reducing CD73 Expression by IL1β-Programmed Th17 Cells Improves Immunotherapeutic Control of Tumors

T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGF beta exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFN gamma production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1 beta instead of TGF beta to program Th17 cells ex vivo. Th17 cells cultured in IL1 beta were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGF beta addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1 beta-cultured Th17 cells. Effector properties of IL1 beta-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGF beta in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy. (C)2014 AACR.