CD47/SIRPα blocking peptide identification and synergistic effect with irradiation for cancer immunotherapy
| Autor: | Wenjie Zhai, Chunxia Chen, Jiangfeng Du, Hongfei Wang, Yanfeng Gao, Ling Jiao, Guanyu Chen, Yahong Wu, Wanqiong Li, Shanshan Gou, Yixuan Sun, Yuanming Qi, Li Yanying, Xiuman Zhou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Immunology CD47 Antigen 03 medical and health sciences Mice 0302 clinical medicine Immune system Cancer immunotherapy Neoplasms medicine Signal-regulatory protein alpha Immunology and Allergy Macrophage Animals Humans RC254-282 radiotherapy Pharmacology Innate immune system Chemistry CD47 Neoplasms. Tumors. Oncology. Including cancer and carcinogens antineoplastic protocols phagocytosis Basic Tumor Immunology Immunotherapy Acquired immune system macrophages 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Molecular Medicine Peptides |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundImmunotherapy has achieved remarkable advances via a variety of strategies against tumor cells that evade immune surveillance. As important innate immune cells, macrophages play important roles in maintaining homeostasis, preventing pathogen invasion, resisting tumor cells and promoting adaptive immune response. CD47 is found to be overexpressed on tumor cells and act as a don’t eat me’ signal, which contributes to immune evasion. Macrophages mediated phagocytosis via blockade CD47/SIRPα (signal regulatory protein alpha) interaction was proved to induce effective antitumor immune response.MethodsA novel peptide pep-20, specifically targeting CD47 and blocking CD47/SIRPα interaction, was identified via high-throughput phage display library bio-panning. The capability to enhance the macrophage-mediated phagocytosis activities and antitumor effects of pep-20 were investigated. The mechanism of pep-20 to induce T-cell response was explored by ex vivo analysis and confirmed via macrophage depleting strategy. The structure-activity relationship and D-amino acid substitution of pep-20 were also studied. The antitumor effects and mechanism of a proteolysis resistant D-amino acid derivate pep-20-D12 combined with irradiation (IR) were also investigated.ResultsPep-20 showed remarkable enhancement of macrophage-mediated phagocytosis to both solid and hematologic tumor cells in vitro, and inhibited tumor growth in immune-competent tumor-bearing mice. Furthermore, pep-20 promoted macrophages to mobilize the antitumor T-cell response with minimal toxicity. Furthermore, systemic administration of the derivate pep-20-D12 showed robust synergistic antitumor efficacy in combination with IR.ConclusionIn summary, these results demonstrated that CD47/SIRPα blocking peptides, pep-20 and its derivate, could serve as promising candidates to promote macrophages-mediated phagocytosis and immune response in cancer immunotherapy. |
| Databáze: | OpenAIRE |
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