Abstract
Although epithelial cell adhesion molecule (EpCAM) has previously been shown to promote tumor progression, the underlying mechanisms remain largely unknown. Here, we report that the EGF-like domain I within the extracellular domain of EpCAM (EpEX) binds EGFR, activating both AKT and MAPK signaling to inhibit forkhead transcription factor O3a (FOXO3a) function and stabilize PD-L1 protein, respectively. Treatment with the EpCAM neutralizing antibody, EpAb2-6, inhibited AKT and FOXO3a phosphorylation, increased FOXO3a nuclear translocation, and upregulated high temperature requirement A2 (HtrA2) expression to promote apoptosis while decreasing PD-L1 protein levels to enhance the cytotoxic activity of CD8+ T cells. In vivo, EpAb2-6 markedly extended survival in mouse metastasis and orthotopic models of human colorectal cancer. The combination of EpAb2-6 with atezolizumab, an anti-PD-L1 antibody, almost completely eliminated tumors. Moreover, the number of CD8+ T cells in combination-treated tumors was increased compared with atezolizumab alone. Our findings suggest a new combination strategy for cancer immunotherapy in patients with EpCAM-expressing tumors. SIGNIFICANCE: This study shows that treatment with an EpCAM neutralizing antibody promotes apoptosis while decreasing PD-L1 protein to enhance cytotoxic activity of CD8+ T cells.
©2020 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / therapeutic use
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Antibodies, Neutralizing / pharmacology
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Antigens, Neoplasm / metabolism
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Antineoplastic Agents / therapeutic use
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Apoptosis
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B7-H1 Antigen / chemistry*
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CD8-Positive T-Lymphocytes / immunology*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / therapy
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Cycloheximide / pharmacology
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Disease Progression*
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Enzyme Activation
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Epithelial Cell Adhesion Molecule / metabolism*
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ErbB Receptors / metabolism*
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Forkhead Box Protein O3 / metabolism*
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Heterografts
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High-Temperature Requirement A Serine Peptidase 2 / metabolism
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Humans
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Transplantation
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Phosphorylation / drug effects
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Programmed Cell Death 1 Receptor / metabolism
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Protein Domains
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Protein Stability / drug effects
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Up-Regulation
Substances
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Antibodies, Monoclonal, Humanized
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Antibodies, Neutralizing
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Antigens, Neoplasm
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Antineoplastic Agents
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B7-H1 Antigen
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Epithelial Cell Adhesion Molecule
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FOXO3 protein, human
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Forkhead Box Protein O3
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Protein Synthesis Inhibitors
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atezolizumab
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Cycloheximide
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2