title: Synthetic RORγt Agonists Enhance Protective Immunity.
abstract: The T cell specific RORγ isoform RORγt 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. 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 TH17 cell proliferation. Here, we show that activation of RORγt 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 RORγt 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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Dharmarajan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Christelle
authors.initials: C
authors.lastname: Doebelin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Garcia-Ordonez
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Novick
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D049109:Cell Proliferation; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists*
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human