Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment

By Mackenzie J. Bender, A. McPherson, Catherine M Phelps, S. Pandey, Colin R Laughlin, Jake H. Shapira, Luzmariel Medina Sanchez, M. Rana, Tanner G. Richie, Tahliyah S. Mims and 15 more. Cell, 2023

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The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor treatment (ICI). 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 antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) 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 bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr’s antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.

Subfields: Biological Psychiatry, Molecular Biology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/8eab54c2758cfcb9a35eb51b118249d57d89b244