DIETARY TRYPTOPHAN CATABOLITE RELEASED BY INTRATUMORAL LACTOBACILLUS REUTERI FACILITATES ANTI-PD-L1 THERAPY

Abstract The gut microbiome has been identified as a critical factor influencing cancer patient responses to immune checkpoint inhibitor (ICI) therapy; however, the underlying mechanisms of how gut microbes modulate ICI therapy efficacy remain enigmatic. Here, we show that gut-commensal Lactobacillus reuteri (L. reuteri) translocates to melanoma tumors where it mediates antitumor interferon-γ-producing CD8 T cell (Tc1 cell) immunity and facilitates ICI therapy via its released aryl hydrocarbon receptor (AhR) ligand, indole-3-aldehyde (I3A). This dietary tryptophan (Trp) catabolite is necessary and sufficient for antitumor immunity, and AhR signaling within CD8 T cells is required for L. reuteri to suppress melanoma growth. Further, a Trp-enriched diet potentiated L. reuteri- and ICI-induced antitumor immunity. Finally, we uncovered a role of I3A in promoting ICI therapy responses and survival in advanced melanoma patients. Collectively, our findings elucidate a novel crosstalk within the tumor microenvironment between the microbial metabolite I3A and CD8 T cells that facilitates ICI therapy efficacy, paving the way for dietary- and probiotic-based cancer therapeutics.