{
  "abstract": "Background Immune checkpoint inhibition (ICI) has shown robust efficacy for a subset of patients with cancer. However, the immunosuppressive tumor microenvironment prevents broader therapeutic efficacy. Here, we sought to understand contributions of the immune landscape, tumor mutational load, tumor viral loads, PD-L1 expression, and intratumoral microbiome in driving immunotherapy resistance.Methods We first performed comprehensive analysis of oropharyngeal head and neck squamous cell carcinomas (HNSCCs) from the CIAO clinical trial. Our findings were validated in 4 additional patient cohorts, and causality mechanistically confirmed using pre-clinical in vitro and in vivo models.Results In the CIAO clinical trial, we found that only the total abundance of intratumoral bacteria successfully predicted response to ICI, with no predictive value from tumor mutation burden, PD-L1, T cell infiltration, or viral load. Notably, we found that total intratumoral bacteria abundance, rather than any specific taxa’s relative abundance, was the critical driver of this immunosuppression. We validated that ability of total intratumoral bacteria to induce ICI resistance in multiple cohorts and cancer types. High intratumoral bacteria abundance was associated with an immunosuppressive tumor immune microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction of intratumoral bacteria abundance in orthotopic models of head and neck squamous cell carcinoma recapitulated immunological associations observed in patient tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PD-L1 immune checkpoint blockade, independent of bacterial species.Conclusions Collectively, these findings demonstrate that total intratumoral bacteria abundance is a key suppressor of anti-tumor immunity and promotes immunotherapy resistance.Ethics Approval All participants gave informed consent to be included in this study. The CIAO clinical trial ( NCT03144778) was overseen by the Institutional Review Board at MD Anderson Cancer Center. Collection of additional samples from Cleveland Clinic were overseen by the Cleveland Clinic Institutional Review Board (IRB# 4311). Mouse studies were overseen by the Cleveland Clinic Institutional Animal Care and Use Committee.",
  "authors": [
    {
      "affiliations": [
        "Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA"
      ],
      "name": "Natalie Silver"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, OH, USA"
      ],
      "name": "Jin Dai"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, OH, USA"
      ],
      "name": "Travis D Kerr"
    },
    {
      "affiliations": [
        "Cleveland Clinic Cancer Center, Cleveland, OH, USA"
      ],
      "name": "Tyler Alban"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Neil Gross"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Andrew G Sikora"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Elias Sayour"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, OH, USA"
      ],
      "name": "Apollo R Stacy"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Christian Jobin"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, OH, USA"
      ],
      "name": "Timothy A Chan"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Renata Ferrarotto"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, OH, USA"
      ],
      "name": "Daniel J McGrail"
    }
  ],
  "title": "1144 Total intratumoral bacteria abundance drives immunosuppression and immunotherapy resistance",
  "uid": "59033fb3-0c04-5de4-94fc-22fcf8c50890"
}