Advantage of extracellular vesicles in hindering the CD47 signal for cancer immunotherapy.

Abstract

The cluster of differentiation 47 (CD47) protein is abundantly expressed on various malignant cells and suppresses the phagocytic function of macrophages and dendritic cells. High CD47 expression levels are correlated with poor cancer survival. Antagonizing CD47 antibodies with potent antitumor effects have been developed in clinical trials, but have critical side effects, inducing anemia and thrombocytopenia. To develop a safe and potent CD47 blockade, we designed extracellular vesicles (EVs) harboring signal regulatory protein alpha (SIPRα)-EV-SIRPα (EVs that express SIPRα). EV-SIRPα showed minimal toxic effects on hematologic parameters and utilized RBCs as delivery vehicles to tumors rather than inducing anemia. EV-SIRPα inhibited ligation of residual CD47 molecules, which attribute to the EV-endocytosis-mediated CD47 depletion and steric hindrance of EV. In an immunologically cold tumor model, EV-SIRPα induced tumor-specific T-cell-mediated antitumor effects. When directly administered to the accessible lesions, EV-SIRPα monotherapy elicited an abscopal effect in the B16F10 tumor model by increasing immune cell infiltration and CD8+-mediated immunity against non-treated tumors. The combinational approach by loading doxorubicin into the EV-SIRPα dramatically reduced the tumor burden and led to 80% complete remission rate. Thus, a potent EV-based CD47 blockade that is hematologically safe, has efficient signaling blocking efficacy, and has systemic antitumor immunity against cancer is recommended.

• Authors: Yoon Kyoung Kim, Yeonsun Hong, Young Rang Bae, Jiyoung Goo, Seong A Kim, Yoonjeong Choi, Gi-Hoon Nam, Minsu Kwon, Seung Gyu Yun, Gyejun Lee, Cherlhyun Jeong, In-San Kim
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 351 Pg. 727-738 (Nov 2022) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 36162554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• CD47 Antigen
• Antigens, Differentiation
• CD47 protein, human

Topics

• Humans
• CD47 Antigen
• Immunotherapy
• Antigens, Differentiation (metabolism)
• Neoplasms (drug therapy, metabolism)
• Macrophages
• Extracellular Vesicles (metabolism)
• Phagocytosis