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

The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells with...

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Published in:Cell 2023-04, Vol.186 (9), p.1846-1862.e26
Main Authors: Bender, Mackenzie J., McPherson, Alex C., Phelps, Catherine M., Pandey, Surya P., Laughlin, Colin R., Shapira, Jake H., Medina Sanchez, Luzmariel, Rana, Mohit, Richie, Tanner G., Mims, Tahliyah S., Gocher-Demske, Angela M., Cervantes-Barragan, Luisa, Mullett, Steven J., Gelhaus, Stacy L., Bruno, Tullia C., Cannon, Nikki, McCulloch, John A., Vignali, Dario A.A., Hinterleitner, Reinhard, Joglekar, Alok V., Pierre, Joseph F., Lee, Sonny T.M., Davar, Diwakar, Zarour, Hassane M., Meisel, Marlies
Format: Article
Language:English
Subjects:
aryl hydrocarbon receptor
CD8-Positive T-Lymphocytes - immunology
Diet
Humans
immune checkpoint inhibitor
Immune Checkpoint Inhibitors
indole-3-aldehyde
Lactobacillus reuteri
Limosilactobacillus reuteri - metabolism
melanoma
Melanoma - therapy
microbial AhR ligands
microbial-host crosstalk
Receptors, Aryl Hydrocarbon - agonists
tryptophan
Tryptophan - metabolism
tumor microbiome
Tumor Microenvironment
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Summary:The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. 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. [Display omitted] •L. reuteri translocates to and drives antitumor Tc1 immunity from within the tumor•Lr-derived indole-3-aldehyde (I3A) improves immune checkpoint inhibitor (ICI) efficacy•I3A induces aryl hydrocarbon receptor-dependent CREB activity, driving Tc1 effector function•Potential role of I3A in promoting ICI response and survival in melanoma patients Commensal bacterium Lactobacillus reuteri migrates to melanoma tumors where its released metabolite enhances antitumor immune responses and improves immune checkpoint inhibitor treatment efficacy.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2023.03.011