Synthetic RORγt Agonists Enhance Protective Immunity

The T cell specific ROR gamma isoform ROR gamma t has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of T(H)17 and T(C)17 cells, cells that have demonstrated antitumor efficacy. ROR gamma t controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of ROR gamma t have been shown to increase the basal activity of ROR gamma t enhancing TH17 cell proliferation. Here, we show that activation of ROR gamma t using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-I, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of ROR gamma t should activate T(C)17/T(H)17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer.