Synthetic ROR?t Agonists Enhance Protective Immunity.

ABSTRACT: The T cell specific ROR? isoform ROR?t has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. ROR?t controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of ROR?t have been shown to increase the basal activity of ROR?t enhancing TH17 cell proliferation. Here, we show that activation of ROR?t using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, 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?t should activate TC17/TH17 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.

SUBMITTER: Chang MR 

PROVIDER: S-EPMC5178133 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature