{
  "abstract": "Background Checkpoint inhibitors have emerged as a standard of care therapy for non-small cell lung cancer (NSCLC). Mutations in STK11 occur in 20% of NSCLC and are associated with poor responsiveness to anti-PD-1 agents, creating an increased need to identify novel therapeutic targets for this tumor subtype.Methods Functional genomic screening utilizing CRISPR-Cas9 is a powerful tool to identify new therapeutic targets in cancer. We applied this technology specifically to STK11-mutant syngeneic tumor models in mice to identify targets which restore sensitivity to anti-PD-1 therapy.Results Knockout of MGAT1, an enzyme critical for maturation of high-mannose N-glycans into hybrid and complex glycan types, was able to reverse STK11-mutant-driven resistance to anti-PD-1 treatment. Parallel in vitro screens using co-culture systems showed that disruption of N-glycosylation was also a powerful mechanism in sensitizing tumor cells to direct killing by antigen-matched CD8 T cells. Our investigation suggests that global disruption of N-glycans likely impacts the ability of T cells to recognize tumor cells. The role of MGAT1 in immune evasion was dependent on its enzymatic activity, making it a promising target for therapeutic small molecule inhibitor development.Conclusions Our work implicates N-glycosylation as a key mediator of immune evasion in STK11 mutant NSCLC and nominates MGAT1 a novel target for therapeutic development to overcome this mechanism.",
  "authors": [
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Kiera Vassallo"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Alvin Lu"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Kasia Handing"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Shangtao Liu"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Binzhang Shen"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Samuel R Meier"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Yi Yu"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Chengyin Min"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Yingnan Chen"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "William Mallender"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Jannik N Andersen"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Wenhai Zhang"
    },
    {
      "affiliations": [
        "Tango Therapeutics, Boston, MA, USA"
      ],
      "name": "Serge Gueroussov"
    }
  ],
  "title": "1225 Inhibition of MGAT1 overcomes STK11-driven immune evasion in non-small cell lung cancer",
  "uid": "37ae22c9-9288-5496-aad0-d2483a3e1a5f"
}