Abstract 1253: Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy

Abstract The use of probiotics by cancer patients is increasing, including amongst those undergoing immune checkpoint inhibitor (ICI) therapy. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances spontaneous antitumor immunity and facilitates ICI therapy in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (L.reuteri) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby facilitating ICI therapy efficacy. Moreover, L.reuteri secreted I3A was both necessary and sufficient for antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated L.reuteri’s ability to restrain melanoma growth. Further, a tryptophan-enriched diet potentiated both L.reuteri- and ICI-induced antitumor immunity. Finally, we provide evidence for a potential role of I3A in promoting ICI therapy efficacy and survival in advanced melanoma patients. Citation Format: Mackenzie Bender, Alex McPherson, Catherine Phelps, Diwakar Davar, Dario A. Vignali, Hassane Zarour, Marlies Meisel. Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy [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 1253.