{
  "abstract": "Background A sedentary lifestyle significantly increases the risk of cancer. In contrast, exercise has been associated with enhanced antitumor immunity and improved immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma. However, the mechanisms through which exercise mediates antitumor effects remain obscure. Here, we show for the first time that exercise-induced changes to the microbiota are a key mechanism by which exercise promotes antitumor immunity via a previously undefined mechanism.Methods In this study, we use a mouse treadmill running model to define the mechanisms by which exercise enhances tumor immunity and ICI efficacy in a translationally relevant BRAF melanoma tumor model which is ICI resistant.Results We first show that exercise-mediated tumor suppression relies upon adaptive immunity, specifically CD8 T cells, and an intact specific pathogen-free microbiota in our model. Strikingly, we show that the compositionally distinct exercised microbiota is sufficient to confer tumor suppression, but must be metabolically active to do so, suggesting a key role for metabolites produced by the exercised microbiota. Accordingly, we find that exercise-microbiota produced metabolites are sufficient to restrain tumor growth in vivo and act directly on CD8 T cells to promote antitumor effector function in vitro. Through targeted and untargeted metabolomics approaches, we identify that exercise changes metabolic output of the microbiota by increasing bacterial 1-carbon metabolism. Accordingly, formate, a short-chain fatty acid intermediate of 1-carbon metabolism, is enriched in cecum contents and serum of exercised mice. In our model, we find that oral administration of formate is sufficient to restrain tumor growth, promote CD8 T cell effector function and STAT1 phosphorylation, and enhance immunotherapy efficacy in a manner dependent on Nuclear Factor Erythroid 2-related factor 2 (Nrf2) signaling. Excitingly, we show that serum formate is linked to prolonged survival and fecal pyruvate formate lyase (pfl) expression is linked to immunotherapy responsiveness in two separate cohorts of melanoma patients. Further, we show that a high-formate producing human microbiota restrains tumor growth upon transplant into mice, suggesting that high fecal formate may act as a biomarker to identify optimal FMT donors.Conclusions Through this study, we have unveiled a previously unrecognized mechanism in which exercise, by modulating the production of a microbiota metabolite, improves ICI efficacy in melanoma. Our study will motivate a new line of investigations leading to novel exercise, precision dietary, and microbial metabolite combinatorial therapeutic strategies to promote the clinical antitumor effect of microbial Nrf2 agonists, such as formate, in immunotherapy-resistant cancer patients.",
  "authors": [
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Catherine M Phelps"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Nathaniel B Willis"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Tingting Duan"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Amanda H Lee"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Yue Zhang"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Colin R Laughlin"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Surya P Pandey"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Daphne Rodriguez"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Alex C McPherson"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Jake H Shapira"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Aaron BI Rosen"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Simran K Randhawa"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Reinhard Hinterleitner"
    },
    {
      "affiliations": [
        "University of Kansas, Manhattan, KS, USA"
      ],
      "name": "Sonny Lee"
    },
    {
      "affiliations": [
        "University of Vienna, Vienna, Vienna, Austria"
      ],
      "name": "Karl-heinz Wagner"
    },
    {
      "affiliations": [
        "University of California Davis, Davis, CA, USA"
      ],
      "name": "Sebastian E Winter"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Jishnu Das"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Joseph F Pierre"
    },
    {
      "affiliations": [
        "UPMC Hillman Cancer Center, Pittsburgh, PA, USA"
      ],
      "name": "Hassane M Zarour"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Giorgio Trinchieri"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Marlies Meisel"
    }
  ],
  "title": "1132 Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity against ICI-resistant melanoma",
  "uid": "03c7ec13-9131-5f5b-b9f4-a382d982770e"
}