Abstract 5099: Anti-tumor effect of DA-4505, a novel AhR antagonist as an immunotherapy in the tumor microenvironment
Authors: Cha Daewon , Kim Dajeong , Cho Jongho , Ryu Chaelim , Jeong Hyeon Uk , Lee Dae Young , Kim Kyu-Hwan , Kim Sunghwa , Kim Jee-Heun , Han Taedong , Doh Hyounmie 
Published: April 2023

Aryl hydrocarbon receptor(AhR) is a ligand-dependent transcription factor that regulates the activity of innate and adaptive immune cells subsequent to binding of numerous endogenous and exogenous ligands. Recently, kynurenine (Kyn), a tryptophan metabolite, has been identified as the most prominent endogenous ligand of AhR, which is constantly secreted into the tumor microenvironment by cancer cells via IDO1 and TDO2. As this secretion is known to cause a broad immunosuppression, AhR is considered to be a central mediator of suppressing immune responses, thereof, a novel target for cancer immunotherapy. In this study, we have discovered a novel small molecule AhR antagonist, DA-4505, and investigated whether it can pursue the restoration of functionally suppressed immune cells in the tumor microenvironment, then, achieve a consequent anti-tumor effect specifically via altering various aspects of tumor microenvironment. DA-4505, AhR antagonist, exhibited high potency (IC50=3 nM) and showed comparable antagonism to Compound B (an AhR antagonist drug candidate being studied in the clinical phase) in both human and mouse hepatocytes. Furthermore, DA-4505 showed superior alleviating activity on benzo[a]pyrene and 2,3,7,8-tetrachlordibenzodioxin (TCDD, an AhR ligand) induced CYP1A1 mRNA level compared to Compound B in mouse livers. Similarly, DA-4505 treatment presented comparable or even better recovery effect on TNF production under Kyn-induced immunosuppressive condition in monocytes of mouse and human compared to Compound B. DA-4505 dose-dependently enhanced activation of human CD8+ T cells comparable to Compound B and rescued IL-2 and IFNγ production under Kyn treated condition. Moreover, DA-4505 specifically polarized macrophages towards inflammatory macrophage phenotype (M1).Oral administration of DA-4505 induced a significant tumor growth inhibition in several murine syngeneic mouse models and was synergistic in combination with anti-PD1 antibody. DA-4505 enhanced the infiltration of M1-macrophage and CD8+ T cells while suppressed the infiltration of M2-macrophage and Treg, thus, presenting anti-tumor effect. Specifically, we confirmed that the anti-tumor effect of DA-4505 is CD8+ T cell-dependent by CD8+ T cell depleted MC38 mouse model. Taken together, our result showed that DA-4505, AhR antagonist, presented its anti-tumor effects in two distinctive but cooperative way into some extent. Firstly, DA-4505 activated stimulatory immune cells such as monocytes, dendritic cells (DC) and effector T cells. Secondly, DA-4505 reduced the immunosuppressive mechanisms by regulating Treg and M2-macrophage. Thus, our data demonstrate the potential of AhR as a promising therapeutic target for cancer immunotherapy as well as proposing DA-4505 as a novel therapeutic agent for both mono and aPD-1 combinatory therapeutic scheme.

Citation Format: Daewon Cha, Dajeong Kim, Jongho Cho, Chaelim Ryu, Hyeon Uk Jeong, Dae Young Lee, Kyu-Hwan Kim, Sunghwa Kim, Jee-Heun Kim, Taedong Han, Hyounmie Doh. Anti-tumor effect of DA-4505, a novel AhR antagonist as an immunotherapy in the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5099.