Dietary tryptophan catabolite released by intratumoral Lactobacillus reuteri facilitates αPD-L1 therapy
Year: 2022
Type: preprint
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.
Source: Research Square
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Gut mucosal type-2 immunity to parasitic infections, G170632743, Role of probiotic Lactobacillus reuteri in orchestrating systemic anti-tumor immunity, G2438032066, G2848036350, G2937968855, Tumor microbiome potentiates cancer immunotherapy in melanoma, G4457027813, G4836508419, G5323996068, Production of Interferon Gamma by Regulatory T Cells Mediates Response to Immunotherapy, G6966134840, Interleukin-35 and the tumor microenvironment, G9000028255, G9000119877, G9000341336, Cancer Immunology Training Program, Systemic immunoregulatory consequences of bacterial translocation during health and disease, Cancer Center Support Grant, Synergies among inhibitory receptors in tolerance and disease
OpenAlex ID: W4280608869