Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells

Demet Candas-Green,Jian Jian Li,Bowen Xie,Colleen Sweeney,Ji Ming Wang,Chong Xian Pan ,David J Grdina,Di Jiang ,Shuli Xia,Tao Li,Kit S Lam,Soheila Azghadi,Lu Zhang,Andrew T M Vaughan ,Ming Fan,Rulong Shen,William J Murphy,Jie Huang,Wei‐Fang Zhou ,Tianyi Gao,Nian Jiang,Cheikh Menaa,Gayle E Woloschak ,Lin Liu,Hong Wu Chen ,Tzu Yin Lin ,Ai‐Jun Wang ,Arta M Monjazeb,Omer M Ozpiskin,Liguo Sun ,Yanhong Zhang,Ralph R Weichselbaum

doi:10.1038/s41467-020-18245-7

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.

Highlights

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
Tumors compared to the counterpart primary tumors by IHC analysis (Fig. 1e). Such CD47-HER2-associated recurrent rates agreed with a worse prognosis in breast cancer (BC) patients with a dual enhancement of CD47 and HER2 compared to patients with high expression of either receptor alone, measured by recurrence-free survival (RFS) or by distant metastasis-free survival (DMFS) (Fig. 1f, g); as well as by the overall survival (OS) in patients with lymph node metastasis (Supplementary Fig. 1a), or in patients with endocrine therapy after surgery (Supplementary Fig. 1b)
We hypothesized that the accumulated amount of CD47 and HER2 on the cell surface is a critical feature of an aggressive phenotype in radioresistant BC cells

Summary

Introduction

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. This study reveals a coordinative transcriptional regulation of CD47 and HER2 in the radioresistant BC cells Expression of both CD47 and HER2 is enhanced in irradiated BC cells, in RTtreated mouse syngeneic breast tumors, and in BC patients with recurrent diseases associated with a poor prognosis. Blocking CD47 enhances macrophages-mediated phagocytosis and suppresses HER2-associated aggressiveness in the radioresistant BC cells, which is recapitulated using mouse syngeneic BC that can be synergistically suppressed by RT with inhibition of both receptors These results demonstrate a latent pro-tumor growth mechanism due to the cross-talking of CD47enhanced immune-avoidance with HER2-promoted intrinsic cell proliferation, causing the aggressive behavior of resistant BC cells. Dual blocking CD47 and HER2 may effectively abolish resistant cancer cells in BC radiotherapy

Methods

Results

Conclusion