{
  "abstract": "Background Heightened tumor Oxidative Phosphorylation (OxPhos) deprives tumor infiltrating T cells of oxygen and results in a tumor microenvironment (TME) saturated with T cell suppressive byproducts such as adenosine, lactate and reactive oxygen species. Thus, dysregulated tumor OxPhos excludes T cell from the TME. Existing OxPhos inhibitors, while effective at diminishing tumor metabolism and proliferation, are toxic to naïve T cells, impede T cell activation and demonstrated minimal therapeutic window in patients highlighting the need for more selective drugs. From gastric cancer biopsies, we identified 10 mitochondrial complex I subunits which were differentially upregulated in cancers when compared to T cells and even normal epithelia. We therefore hypothesized that it might be possible to target tumor upregulated Complex I subunits while limiting toxicity and sparing T cell driven anti-tumor immunity.Methods Ten mitochondrial Complex I subunits were knocked down using lentiviral shRNA vectors in MC38 murine colorectal cancer and B3Z T cell hybridomas. Splenic T cells from NDUFS4 knockout mice were used to assess impact of NDUFS4 loss on function. Impact of knocking down complex I subunits on viability, proliferation, mitochondrial health, bioenergetics and activity were assessed using Incucyte, transmission electron microscopy, Seahorse (Agilent) and flow cytometry.Results In MC38 tumor cells, knockdown of tumor overexpressed Complex I subunits in the N module (NDUFA7, NDUFS4) significantly impairs proliferation, mitochondrial health and metabolism. At the same time, surface MHC-I levels and antigen presentation increase suggesting enhanced sensitivity to T cell cytotoxicity. In contrast, knockdown of NDUFA7 in B3Zs or lack of NDUFS4 in primary T cells respectively yields unhindered activation, cytotoxicity and proliferation unlike the metabolic and functional suppression observed with existing OxPhos inhibitors. In vivo, NDUFA7 knockdown MC38 tumors show significantly delayed tumor progression, elevated intratumoral CD8 T cell proliferation and decreased PDL1 expression in the myeloid stroma suggesting enhanced sensitivity to anti-tumor immunity.Conclusions We discovered exaggerated tumor OxPhos utilization of the Complex I subunits NDUFA7 and NDUFS4. Tumor specific knockdown of these subunits impaired tumor proliferation and metabolism and increased immune sensitivity in vivo. In contrast, T cell function and metabolism appeared unimpaired by NDUFA7 knockdown or NDUFS4 loss. These studies reveal a mechanism of selective tumor OxPhos inhibition which may increase T cell metabolic fitness in the TME while leaving tumors crippled and exposed to immune cytotoxicity.",
  "authors": [
    {
      "affiliations": [
        "UT MD Anderson Cancer Center UTHealth GSBS, Houston, TX, USA"
      ],
      "name": "Krithikaa Rajkumar Bhanu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Priyamvada Jayaprakash"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Waikin Chan"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Linghua Wang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Michael A Curran"
    }
  ],
  "title": "760 Tumor oxidative metabolism exhibits atypical dependence on two mitochondrial complex I subunits that are dispensable for T cell function",
  "uid": "46401d10-dbee-512b-94b4-5e32d616cd07"
}