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Abstract Background: The Aryl hydrocarbon receptor (AhR) is one of the most predominant regulators of cancer metabolism. AhR plays a crucial role in inhibiting the activation of immune cells and promoting the growth of tumor cells. Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy in combination with anti-PD-1. Methods: To explore the anti-tumor effects, DA-4505 was administered at a daily dose of 10 mg/kg either alone or in combination with anti-PD-1 (10 mg/kg) in a syngeneic mouse model. Tumor volume, survival rates, and metastasis were measured, and immune profiles were evaluated using mIHC, flow cytometry, and scRNAseq. Results: The synergistic anti-tumor effects of the DA-4505 and aPD-1 combination therapy were observed across four mouse tumor models (CT26, 4T1, LLC, TC1). The combination group demonstrated a significant improvement in anti-tumor efficacy compared to the monotherapy groups. Despite the moderate response of aPD-1 in the CT26 colon tumor model, the combination group displayed heightened anti-tumor effects through increase in CD8 T cell activity (P0. 05). In the LLC and TC1 lung cancer models, the combination therapy demonstrated improved anti-tumor effects and survival rates (P0. 001). Notably, the LLC model exhibited a significant increase in M1-type macrophages, while the TC1 model showed a significant augmentation in functional markers of CD3+ T cells within the combination group (P0. 05). In both models, there was a significant reduction in the ratio of immunosuppressive M-MDSC and PMN-MDSC in the combination group. Immune depletion assays elucidated that DA-4505 mediated anti-tumor effects by increase in CD8+ T cells, NK cells, and macrophages in the CT26 model. In contrast, the LLC model exhibited the contribution of macrophages and CD4+ T cells to anti-tumor effects in the combination group (P0. 05). To assess the impact on metastasis inhibition, an orthotopic model of 4T1 mouse tumor was established, revealing a significantly increased anti-tumor effects and survival rate in the combination group, accompanied by a reduced lung metastasis ratio. H Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4039.
Kim et al. (Fri,) studied this question.