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

Mackenzie J Bender; Alex C McPherson; Catherine M Phelps; Surya P Pandey; Colin R Laughlin; Jake H Shapira; Luzmariel Medina Sanchez; Mohit Rana; Tanner G Richie; Tahliyah S Mims; Angela M Gocher-Demske; Luisa Cervantes-Barragan; Steven J Mullett; Stacy L Gelhaus; Tullia C Bruno; Nikki Cannon; John A McCulloch; Dario A A Vignali; Reinhard Hinterleitner; Alok V Joglekar; Joseph F Pierre; Sonny T M Lee; Diwakar Davar; Hassane M Zarour; Marlies Meisel

doi:10.1016/j.cell.2023.03.011

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

Cell. 2023 Apr 27;186(9):1846-1862.e26. doi: 10.1016/j.cell.2023.03.011. Epub 2023 Apr 6.

Authors

Mackenzie J Bender¹, Alex C McPherson², Catherine M Phelps³, Surya P Pandey¹, Colin R Laughlin¹, Jake H Shapira¹, Luzmariel Medina Sanchez³, Mohit Rana¹, Tanner G Richie⁴, Tahliyah S Mims⁵, Angela M Gocher-Demske⁶, Luisa Cervantes-Barragan⁷, Steven J Mullett⁸, Stacy L Gelhaus⁸, Tullia C Bruno⁹, Nikki Cannon¹⁰, John A McCulloch¹⁰, Dario A A Vignali⁹, Reinhard Hinterleitner¹¹, Alok V Joglekar¹², Joseph F Pierre⁵, Sonny T M Lee⁴, Diwakar Davar¹³, Hassane M Zarour¹⁴, Marlies Meisel¹⁵

Affiliations

¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Division of Biology, Kansas State University, Manhattan, KS, USA.
⁵ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
⁷ Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.
⁸ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁰ Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹³ Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁵ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: marlies@pitt.edu.

Abstract

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.

Keywords: Lactobacillus reuteri; aryl hydrocarbon receptor; immune checkpoint inhibitor; indole-3-aldehyde; melanoma; microbial AhR ligands; microbial-host crosstalk; tryptophan; tumor microbiome.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / immunology
Diet
Humans
Immune Checkpoint Inhibitors
Limosilactobacillus reuteri* / metabolism
Melanoma* / therapy
Receptors, Aryl Hydrocarbon / agonists
Tryptophan / metabolism
Tumor Microenvironment*

Substances

Immune Checkpoint Inhibitors
Tryptophan
Receptors, Aryl Hydrocarbon

Abstract

Publication types

MeSH terms

Substances

Grants and funding