Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer

CD47型 癌症研究 吉非替尼 肺癌 肿瘤微环境 癌细胞 生物 巨噬细胞极化 表皮生长因子受体 癌症 免疫学 免疫系统 巨噬细胞 医学 体外 病理 肿瘤细胞 生物化学 遗传学
作者
Jiaye Lu,Jingwei Li,Ziyou Lin,Huaxuan Li,Linlin Lou,Wen Ding,Shumin Ouyang,Yonghui Wu,Yuanzhen Wen,Xiaobing Chen,Peibin Yue,Yuanxiang Wang,Peiqing Liu,Jin-Jian Lu,Jian Zhang,Weineng Feng,Xiaolei Zhang
出处
期刊:Cancer Letters [Elsevier]
卷期号:564: 216205-216205 被引量:28
标识
DOI:10.1016/j.canlet.2023.216205
摘要

Cross-talk between the tumor microenvironment (TME) and cancer cells plays an important role in acquired drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The role of tumor-associated macrophages (TAMs), the major component of the TME, in acquired resistance remains unclear. In this study, M2-like reprogramming of TAMs and reduced phagocytosis by macrophages were observed in gefitinib-resistant lung cancer cells and tumor xenografts. CD47 was upregulated in TKI-resistant lung cancer cells, and M2 macrophage polarization and cancer cell escape from macrophage phagocytosis were enhanced. Culture medium from TKI-resistant cells led to metabolic reprogramming of TAMs. STAT3 was associated with CD47 expression in TKI-resistant lung cancer cells. Genetic and pharmacological inhibition of STAT3 enhanced the phagocytic activity of TAMs and alleviated the acquired resistance to EGFR-TKIs via inhibiting the CD47-SIRPα signaling axis and M2 polarization in the co-culture system. Moreover, STAT3 transcriptionally regulated CD47 expression by binding to consensus DNA response elements in the intron of the CD47 gene. Furthermore, the combination of gefitinib with a STAT3 inhibitor and an anti-CD47 monoclonal antibody alleviated the acquired resistance to gefitinib in vitro and in vivo. Collectively, our study reveals the role of TAM reprogramming and the CD47-SIRPα axis in acquired EGFR-TKI resistance and provides a novel therapeutic strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer.
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