{
  "abstract": "Background Epithelial cell adhesion molecule (EpCAM) is a pleotropic transmembrane glycoprotein comprising an extracellular domain (EpEX), a single transmembrane domain, and an intracellular domain (EpICD). For several types of cancer, high EpCAM expression is associated with tumor progression, metastasis, immune evasion, and overall poor prognosis.Methods The signaling of EpCAM were evaluated by ELISA, flow cytometry, immunohistochemistry, Western blotting and qRT-PCR. The biofunctions were analyzed by using proliferation, invasion, stemness analysis, and animal model.Results We found that the EpCAM promotes immune suppressive microenvironment in cancer. EpCAM induces T cell exhaustion that is known to be critical for that tumor cells to exhibit escaping natural immunity. In vivo syngeneic models confirm that excess expressions of EpCAM on tumor cell enforce overproduction of key cytokines such as IFN-γ and IL-2 that ultimately are involved in T cell exhaustion to create immune suppressive microenvironment. EpCAM signaling also increases TNF-α expression and induces TNF-α cleavage, and clarify the crosstalk between EpCAM and TNF-α to regulate ERK-EGR1 axis signaling. Furthermore, we found that EpEX induced phosphorylation of EGFR, HGFR and Wnt receptors in cancer cells to promote cell growth, invasion and stemness activity. EGF-like domain I of EpEX binds EGFR, activating ERK signaling to stabilize PD-L1 protein. Treatment with the EpCAM neutralizing antibody decreases PD-L1 protein level to enhance the cytotoxic activity of CD8+ T cells. In vivo, EpCAM neutralizing antibody inhibits tumor growth, and its combination with the anti-PD-L1 antibody Atezolizumab almost completely eliminates tumors in mouse models. Moreover, the number of CD8+ T cells in combination-treated tumor tissues was increased compared to Atezolizumab treatment alone.Conclusions Thus, shutting down EpCAM signaling kills tumor cells and prevents their escape from immune surveillance. Our findings suggest a new combination strategy for cancer immunotherapy in patients with EpCAM-expressing tumors.",
  "authors": [
    {
      "affiliations": [
        "Academia Sinica, Nangang, Taipei, Taiwan"
      ],
      "name": "Chi-Chiu Lee"
    },
    {
      "affiliations": [
        "Academia Sinica, Nangang, Taipei, Taiwan"
      ],
      "name": "Sushree Shankar Panda"
    },
    {
      "affiliations": [
        "Academia Sinica, Nangang, Taipei, Taiwan"
      ],
      "name": "Yi-Jen Su"
    },
    {
      "affiliations": [
        "Academia Sinica, Nangang, Taipei, Taiwan"
      ],
      "name": "Tsai-Ming Lu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Shao-Hsi Hung"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Cassian Yee"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Stephen Y Lai"
    },
    {
      "affiliations": [
        "Academia Sinica, Nangang, Taipei, Taiwan"
      ],
      "name": "Han-Chung Wu"
    }
  ],
  "title": "1272 EpCAM signaling promotes immunosuppressive tumor microenvironment and a novel therapeutic antibody enhances anti-tumor immunity",
  "uid": "5f12340f-0f67-5e0d-b7af-1cfac0148944"
}