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放疗与化疗相比，全身副作用相对较少。17项随机临床研究荟萃分析表明，保乳术后放疗与未放疗的乳腺癌患者相比，10年局部复发或远处转移风险、15年乳腺癌死亡风险显著较低。既往研究结果表明，免疫靶向治疗可增强乳腺癌放疗的效果。不过，放疗也可诱发肿瘤细胞免疫抑制因子，造成放疗无效，具体机制尚不明确。 2020年9月14日，英国《自然》旗下《自然通讯》在线发表中国湖南长沙中南大学湘雅医院、美国戴维斯加利福尼亚大学、凯撒医疗中心、俄亥俄州立大学、西北大学费恩伯格医学院、芝加哥大学、国家癌症研究所、霍普金斯大学的研究报告，探讨了放疗无效乳腺癌细胞的免疫抑制机制及其对策。 该研究发现，放疗无效的乳腺癌细胞和经过放疗的小鼠同基因乳腺癌细胞表面同时高表达人类表皮生长因子受体HER2以及CD47，CD47向巨噬细胞表面的信号调节蛋白SIRPα发出“别吃我”信号，可避免肿瘤细胞被巨噬细胞吞噬。这两种受体同时高表达常见于生存结局较差的乳腺癌复发患者。CD47优先高表达于HER2阳性乳腺癌细胞，阻断CD47或HER2可抑制这两种受体的肿瘤细胞克隆形成能力，并且增强巨噬细胞的吞噬作用。利用CRISPR基因编辑技术同时剔除CD47和HER2的编码基因，不仅可抑制肿瘤细胞的克隆形成能力，而且可增强巨噬细胞对肿瘤细胞的攻击能力。此外，CD47抗体＋HER2抗体与放疗对于控制同基因小鼠乳腺肿瘤具有协同作用。 因此，该研究结果表明，放疗无效的乳腺癌由CD47的抗吞噬作用结合HER2的促增殖作用所致，对CD47和HER2进行双重阻断，可消除放疗无效的乳腺癌细胞。 Nat Commun. 2020 Sep 14. Online ahead of print. 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, Jian Jian Li. University of California Davis, Sacramento, CA, USA; Xiangya Hospital, Central South University, Changsha, Hunan, China; Kaiser Permanente Medical Center Vallejo and Vacaville, Vallejo, CA, USA; Ohio State University, Columbus, OH, USA; Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; The University of Chicago, Chicago, IL, USA; National Cancer Institute, Frederick, MD, USA; Johns Hopkins School of Medicine, Baltimore, MD, USA. 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. DOI: 10.1038/s41467-020-18245-7
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