The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer
| Autor: | Yiwen Liu, Luoyi Chu, Xiusen Zhang, Ying Zhao, Xiaochen Hu, Xiang Yuan, Di Zhao, Yibo Guo, Desheng Zhai, Dejiu Kong, Lingyun Sun, Chengbiao Lu, Shupei Liu, Jinyu Kong, Feng Ren, Xurong Hou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Adoptive cell transfer Receptor ErbB-2 Antigen presentation Breast Neoplasms lcsh:RC254-282 Immunophenotyping 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Immune system Antineoplastic Agents Immunological Lymphocytes Tumor-Infiltrating Phagocytosis Trastuzumab Cell Line Tumor medicine Macrophage Animals Humans skin and connective tissue diseases Immune Checkpoint Inhibitors neoplasms Mice Knockout business.industry Macrophages Antibody-Dependent Cell Cytotoxicity Drug Synergism ADCP HER2+ breast cancer V-Set Domain-Containing T-Cell Activation Inhibitor 1 medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Xenograft Model Antitumor Assays 030104 developmental biology B7-H4 030220 oncology & carcinogenesis Cancer cell Humanized mouse Cancer research Female Disease Susceptibility business medicine.drug |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 11, Pp 539-553 (2020) |
| ISSN: | 1476-5586 |
| Popis: | Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2+ breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2+ murine breast cancer (BC) cells in immunocompetent mouse models, a human HER2+ BC xenograft in an immune humanized mouse model, and human PDXs involving adoptive transfer of autologous macrophages to simulate an endogenous mammary tumor-immune microenvironment. Our study demonstrated that trastuzumab greatly and consistently increased macrophage frequency and tumor-cell phagocytosis, and that concurrent knockdown of B7-H4 by a neutralizing antibody increased immune cell infiltration and promoted an antitumor phenotype. Furthermore, neoadjuvant trastuzumab therapy significantly upregulated B7-H4 in the cancer-infiltrating macrophages of HER2+ BC patients, which predicted poor trastuzumab response. We suggest that strategies to specifically enhance ADCP activity might be critical to overcoming resistance to HER2 mAb therapies by inhibiting tumor growth and potentially enhance antigen presentation. Furthermore, these results advance the understanding of macrophage plasticity by uncovering a dual role for ADCP in macrophages involving elimination of tumors by engulfing cancer cells while causing a concomitant undesired effect by upregulating immunosuppressive checkpoints. |
| Databáze: | OpenAIRE |
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