Phelps et al. investigated mechanisms underlying the positive benefits of exercise on ICI efficacy. In preclinical melanoma, adenocarcinoma, and lymphoma models, exercise promoted functional changes in the gut microbiome, resulting in increased production of the metabolite formate. Mechanistically, microbial formate boosted antigen-specific cytotoxic CD8+ T cell function (Tc1) via Nrf2, which was critical for formate-enhanced Tc1 immunity in vitro and in vivo. Microbial sequencing data from stool samples of anti-PD-1-treated patients with melanoma revealed high formate-producing microbiota enhanced tumor suppression and promoted robust antitumor immunity.
Contributed by Katherine Turner
ABSTRACT: Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of
Author Info: (1) 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. (2) Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA. (3) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) 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. (5) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China. (6) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (9) Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Joint CMU-Pitt PhD Program in Computational Biology, Carnegie Mellon-University of Pittsburgh, Pittsburgh, PA, USA. (10) 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. (11) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (13) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (14) Division of Biology, Kansas State University, Manhattan, KS, USA. (15) Division of Biology, Kansas State University, Manhattan, KS, USA. (16) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (17) Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA. (18) Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Vienna, Austria. (19) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (20) Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (21) 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. (22) 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. (23) Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (24) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (25) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. (26) Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (27) Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (28) Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. (29) Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (30) Division of Biology, Kansas State University, Manhattan, KS, USA. (31) Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Research Platform Active Ageing, University of Vienna, Vienna, Austria. (32) Department of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA. (33) Department of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA. (34) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (35) Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA; Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA. (36) Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (37) 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.
