RORγt is a master transcription factor, which regulates the proliferation and functionality of Type 17 T-cells (TH17 and Tc17). Recent nonclinical studies have shown that in addition to promoting effector differentiation, stemness and plasticity, RORγt also inhibits Treg differentiation, an important component of suppressive tumor microenvironment (TME). Therefore, stimulation of RORγt by synthetic, small-molecule agonists holds promise as an immunotherapy. We tested the effects of a RORγ agonist (LYC-54143; 100 mg/kg BID given continuously till the end of study) on the tumor growth and survival in mice in combination with a tumor antigen-specific vaccine (3 doses, one week apart), which is required for proper priming in this model. We found that the RORγ agonist resulted in a highly significant enhancement of the antitumor effect delaying the tumor growth (p≤0.001 at day 21 compared to vaccine alone treatment) and prolonging survival. At day 36 after tumor implantation, 80% of mice survived in the RORγ agonist + vaccine treatment group compared to 0% survival following RORγ agonist or vaccine alone treatments. Immunologically, we found that RORγ agonist treatment led to a significant decrease in the numbers of Tregs and a significant increase in IL-17+ IFNγ+ T cells in the TME. Moreover, RORγ agonist treatment led to a significant increase in the numbers of T cells including increased antigen-specific CD8+ T-cells in the TME. Interestingly, scheduling RORγ agonist before or with the vaccine demonstrated comparable antitumor activity, suggesting that the scheduling of RORγ agonist treatment does not affect the therapeutic outcomes. These results show that an RORγ agonist can enhance the antitumor immune response by enhancing effector functions and by decreasing immune suppression in the TME by increasing cytokine production and switching the differentiation of immune-suppressive Tregs to effector Th17 cells and support that RORγ agonists are promising immune-modulatory agents in cancer.
Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3762.