Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer
Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer
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DOI：
10.1016/j.canlet.2023.216205
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发表时间：
2023-05-06
期刊：
影响因子：
9.7
通讯作者：
Zhang，Xiaolei
中科院分区：
文献类型：
--
作者：
Lu，Jiaye;Li，Jingwei;Zhang，Xiaolei
肿瘤微环境（TME）和癌细胞之间的相互作用在对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的获得性耐药中起着重要作用。肿瘤相关巨噬细胞（TAM），TME的主要成分，在获得性耐药中的作用仍不清楚。在这项研究中，在吉非替尼耐药肺癌细胞和肿瘤异种移植物中观察到TAM的M2样重编程和巨噬细胞的吞噬作用降低。TKI耐药肺癌细胞中CD 47上调，M2巨噬细胞极化和癌细胞逃避巨噬细胞吞噬作用增强。来自TKI抗性细胞的培养基导致TAM的代谢重编程。STAT 3与TKI耐药肺癌细胞中的CD 47表达相关。STAT 3的遗传和药理学抑制增强TAM的吞噬活性，并通过抑制CD 47-SIRPα信号轴和共培养系统中的M2极化来减轻对EGFR-TKI的获得性耐药性。此外，STAT 3通过与CD 47基因内含子中的共有DNA应答元件结合来转录调节CD 47的表达。此外，吉非替尼与STAT 3抑制剂和抗CD 47单克隆抗体的组合减轻了体外和体内对吉非替尼的获得性耐药性。总的来说，我们的研究揭示了TAM重编程和CD 47-SIRPα轴在获得性EGFR-TKI耐药中的作用，并提供了一种新的治疗策略来克服肺癌对EGFR-TKI的获得性耐药。
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.