EpCAM Signaling Promotes Tumor Progression and Protein Stability of PD-L1 through the EGFR Pathway
| Autor: | Mei-Ying Liao, Jun-Kai Lai, Kai-Chi Chen, Yi-Ting Chuang, Han-Chung Wu, William Wei-Fu Tsuei, Shao-Hsi Hung, Kang-Hao Liang, Hao-Nien Chen, Chun-Hsin Lan |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Programmed Cell Death 1 Receptor Apoptosis CD8-Positive T-Lymphocytes B7-H1 Antigen chemistry.chemical_compound Mice 0302 clinical medicine Cancer immunotherapy Cytotoxic T cell Cycloheximide Phosphorylation Protein Synthesis Inhibitors Protein Stability Forkhead Box Protein O3 Epithelial cell adhesion molecule High-Temperature Requirement A Serine Peptidase 2 Epithelial Cell Adhesion Molecule Up-Regulation ErbB Receptors Oncology 030220 oncology & carcinogenesis Disease Progression Heterografts Signal transduction Mitogen-Activated Protein Kinases Colorectal Neoplasms Signal Transduction Antineoplastic Agents Antibodies Monoclonal Humanized 03 medical and health sciences Protein Domains Atezolizumab Antigens Neoplasm Cell Line Tumor medicine Animals Humans Protein kinase B Cell Nucleus Antibodies Neutralizing Enzyme Activation 030104 developmental biology chemistry Tumor progression Cancer research Proto-Oncogene Proteins c-akt CD8 Neoplasm Transplantation |
| Zdroj: | Cancer research. 80(22) |
| ISSN: | 1538-7445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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