Assessment of a Novel RAR-γ Selective Agonist in vitro and in Combination Treatment With Immune Checkpoint Inhibition in vivo Using a Syngeneic Murine Lung Cancer Model

Abstract

All-trans retinoic acid (ATRA), an active metabolite of vitamin A (VA) and a pan-retinoic acid receptor (RAR) agonist, binds to RAR in the nucleus and signals induction or suppression of target genes. Colleagues previously observed that in vivo treatment of ATRA reduced BP (human melanoma) and ED1SQ4 (murine lung cancer) tumor growth in immunocompetent mice but not in immunodeficient mice, suggesting that the anti-tumor effects are mediated by the immune system. However, treatment of ATRA did not cooperate with immune checkpoint inhibition (anti-PD1) in vivo to further reduce tumor growth. In this study, we determined the effects of compound IRX4647, a novel RAR-γ selective agonist, treatment in vitro and in combination treatment with immune checkpoint inhibition (anti-PD-L1) in vivo. Our results showed that IRX4647 treatment in vitro altered growth and RAR/retinoid X receptor (RXR) expression differently in various lung cancer cell lines. Furthermore, IRX4647 cooperated with anti-PD-L1 in vivo by significantly reducing tumor volume in a 344SQ syngeneic murine model. We identified IL-5 and IL13 as immunophenotypic markers present in murine plasma and tumor tissue after treatment with the combination regimen. The precise mechanism related to the observation is still under investigation. This study provided insight in using a novel RAR-γ selective agonist in combination with immune checkpoint inhibition in vivo as an effective immunotherapy for lung cancer.