Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells

Author:

Candas-Green Demet,Xie Bowen,Huang JieORCID,Fan Ming,Wang AijunORCID,Menaa Cheikh,Zhang Yanhong,Zhang Lu,Jing Di,Azghadi Soheila,Zhou Weibing,Liu Lin,Jiang Nian,Li Tao,Gao Tianyi,Sweeney Colleen,Shen Rulong,Lin Tzu-yin,Pan Chong-xian,Ozpiskin Omer M.,Woloschak Gayle,Grdina David J.,Vaughan Andrew T.,Wang Ji Ming,Xia Shuli,Monjazeb Arta M.,Murphy William J.ORCID,Sun Lun-Quan,Chen Hong-Wu,Lam Kit S.,Weichselbaum Ralph R.,Li Jian JianORCID

Abstract

AbstractAlthough the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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