Dual Inhibition Of Cd47 And Her2 To Radiosensitize Breast Cancer Cells

Accumulating studies are aimed to combine immunoregulation with the standard of treatment such as radiotherapy in anti-cancer therapy. A potential cross resistance of tumor cells will be a barrier in furthering the long-term control by such combined treatment. CD47, an immunoglobulin-like transmembrane protein, enables cancer cells to escape the immune surveillance by flagging them with a ‘don’t eat me’ signal, which is recognized by the signal regulatory protein α (SIRPα) on macrophages. Here, we report that CD47 expression is enhanced by radiation in breast cancer cells and in vivo irradiated xenograft tumors via NF-κB regulation. In addition, CD47 and HER2 are co-induced by radiation and CD47 expression is specially enhanced by radiation in HER2-expressing cells. Contrasted with primary tumors, co-expression of CD47 and HER2 is elevated in the recurrent breast tumors. Anti-HER2 treatment inhibits CD47 transcription and protein expression with increased macrophage phagocytosis. Likewise, anti-CD47 not only augments macrophage phagocytosis but also reduces the capacity of tumorsphere formation. Radiation with anti-CD47 synergistically suppresses clonogenic survival and the maximal inhibition was achieved by dual inhibition of CD47 and HER2 with radiation. The synergy of in vivo tumor inhibition is established in mouse breast tumor model via local tumor radiotherapy combined with anti-CD47 treatment. These results demonstrate that the HER2-NF-κB-CD47 loop is responsible the cross-resistance of breast tumor against immune surveillance and radiation. Thus dual inhibition of CD47 and HER2 is a potential target to enhance tumor response to immune-radiotherapy. Funding: This study was partially supported by National Cancer Institute RO1 grant R01CA213830-01 (JJL). Note: This abstract was not presented at the meeting. Citation Format: Demet Candas, Lu Zhang, Cheikh Menaa, Ming Fan, Yanhong Zhang, Lin Liu, Weibing Zhou, Soheila Azghadi, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Andrew T. Vaughan, Ji Ming Wang, Hong-Wu Chen, Kit Lam, Lun-Quan Sun, Arta M. Monjazeb, William J. Murphy, Jian Jian Li. Dual inhibition of CD47 and HER2 to radiosensitize breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2017-LB-226