{
  "abstract": "Background ERBB2/HER2 is overexpressed or mutated in ~15% of gastric cancers due to amplification or mutation of the ERBB2 locus. While the tumor cell-intrinsic consequences of ERBB2 overexpression are well understood, much less is known about its effects on the tumor microenvironment.Methods We have developed genetically engineered ectopic and orthotopic syngeneic models of organoid-based gastric cancer that have allowed us to study the tumor microenvironment of ErbB2-overexpressing tumors, using spectral flow cytometry, single cell RNA sequencing, and TCR repertoire sequencing. Interventions such as anti-Erbb2 and anti-PD1 antibody treatments were used as well.Results We find that ErbB2 drives the infiltration of CD4 + and CD8+ T-cells, which express granzymes, FasL, and surface markers indicating chronic activation, and in the case of CD8+ T-cells, have undergone clonal expansion. The adoptive transfer of T-cells sorted from ErbB2-overexpressing tumors reduces the growth of ErbB2-expressing, but not control tumors in T-cell-deficient recipients. PD-1-specific checkpoint blockade synergizes with an ErbB2-targeting antibody to reduce the growth of ErbB2-expressing, but not control tumors. Mechanistically, ErbB2 overexpression results in micronuclei formation and the transcriptional activation of numerous interferon-responsive genes in vitro and in vivo; mice lacking the type I interferon receptor show higher engraftment rates and lower T-cell infiltration than wild-type controls.Conclusions The combined data indicate that ErbB2, perhaps by driving micronuclei formation, has immunogenic properties that manifest in the form of increased T-cell infiltration and expansion, which can be exploited therapeutically by combining PD1-directed checkpoint blockade with ErbB2-targeted therapy.",
  "authors": [
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Jiazhuo He"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Lydia Kirsche"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Zuzana Nascakova"
    },
    {
      "affiliations": [
        "Department of Medical Oncology and Hematology, University of Zürich and University Hospital Zürich, Zurich, Switzerland"
      ],
      "name": "Francesco Manfredi"
    },
    {
      "affiliations": [
        "Department of Medical Oncology and Hematology, University of Zürich and University Hospital Zürich, Zurich, Switzerland"
      ],
      "name": "Chiara F Magnani"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Giovanni Papa"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Flora Azizi"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland",
        "Functional Genomics Center Zürich, University of Zürich and Federal Institute of Technology Zürich, Zürich, Switzerland"
      ],
      "name": "Peter Leary"
    },
    {
      "affiliations": [
        "Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland"
      ],
      "name": "Anne Müller"
    }
  ],
  "title": "Genetically engineered ErbB2 overexpression sensitizes organoid-derived tumors to checkpoint inhibition in a syngeneic model of gastric cancer",
  "uid": "5e95eee1-d1e6-5e9a-8547-90b9ad8eba41"
}