Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells

Demet Candas-Green, Bowen Xie, Jie Huang, Ming Fan, Aijun Wang, Cheikh Menaa, Yanhong Zhang, Lu Zhang, Di Jing, Soheila Azghadi, Weibing Zhou, Lin Liu, Nian Jiang, Tao Li, Tianyi Gao, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Omer M. Ozpiskin, Gayle Woloschak, David J. Grdina, Andrew T. Vaughan, Ji Ming Wang, Shuli Xia, Arta M. Monjazeb, William J. Murphy, Lun-Quan Sun, Hong-Wu Chen, Kit S. Lam, Ralph R. Weichselbaum and Jian Jian Li ()
Additional contact information
Demet Candas-Green: University of California Davis
Bowen Xie: University of California Davis
Jie Huang: University of California Davis
Ming Fan: University of California Davis
Aijun Wang: University of California Davis
Cheikh Menaa: University of California Davis
Yanhong Zhang: Kaiser Permanente Medical Center Vallejo and Vacaville
Lu Zhang: University of California Davis
Di Jing: University of California Davis
Soheila Azghadi: University of California Davis
Weibing Zhou: University of California Davis
Lin Liu: University of California Davis
Nian Jiang: University of California Davis
Tao Li: University of California Davis
Tianyi Gao: University of California Davis
Colleen Sweeney: University of California Davis
Rulong Shen: Ohio State University
Tzu-yin Lin: University of California Davis
Chong-xian Pan: University of California Davis
Omer M. Ozpiskin: University of California Davis
Gayle Woloschak: Northwestern University, Feinberg School of Medicine
David J. Grdina: The University of Chicago
Andrew T. Vaughan: University of California Davis
Ji Ming Wang: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute
Shuli Xia: Johns Hopkins School of Medicine
Arta M. Monjazeb: University of California Davis
William J. Murphy: University of California Davis
Lun-Quan Sun: Xiangya Hospital, Central South University
Hong-Wu Chen: University of California Davis
Kit S. Lam: University of California Davis
Ralph R. Weichselbaum: The University of Chicago
Jian Jian Li: University of California Davis

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Although 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.

Date: 2020
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DOI: 10.1038/s41467-020-18245-7

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