title: Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity.
abstract: RORγt is the key transcription factor controlling the development and function of CD4+Th17 and CD8+Tc17 cells. Across a range of human tumors, about 15% of the CD4+T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ-/- T cells, underscoring the selective on-target activity of the compounds.In vitrotreatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1in vivo. Thein vitroeffects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer.
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Xikui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Moisan
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesch
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Chauncey
authors.initials: C
authors.lastname: Spooner
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Morgan
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Zawidzka
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mertz
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Dick
authors.initials: D
authors.lastname: Bousley
authors.affiliation: Medical University of South Carolina, Hollings Cancer Center , Charleston, SC, USA.
authors.forename: Kinga
authors.initials: K
authors.lastname: Majchrzak
authors.affiliation: University of Michigan, School of Medicine , Ann Arbor, MI, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Van Huis
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Skalitzky
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hurd
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Toogood
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
authors.affiliation: Medical University of South Carolina, Hollings Cancer Center , Charleston, SC, USA.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.affiliation: University of Michigan, School of Medicine , Ann Arbor, MI, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: Lycera Corp , Ann Arbor, MI, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Carter
keywords: Adoptive cell therapy; PD-1; RORγ; Tc17; Th17; co-inhibitory receptors; co-stimulatory receptors; immunotherapy