Synthetic RORγt Agonists Enhance Protective Immunity

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• 作者：Mi Ra Chang ; Venkatasubramanian Dharmarajan ; Christelle Doebelin ; Ruben D. Garcia-Ordonez ; Scott J. Novick ; Dana S. Kuruvilla ; Theodore M. Kamenecka ; Patrick R. Griffin
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：April 15, 2016
• 年：2016
• 卷：11
• 期：4
• 页码：1012-1018
• 全文大小：449K
• 年卷期：0
• ISSN：1554-8937

文摘

The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of T_H17 and T_C17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing T_H17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of T_H17 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 T_H17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate T_C17/T_H17 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.