通过 STAT3/CD47-SIRPα 轴对 TAM 进行重编程可促进肺癌对 EGFR-TKI 的获得性耐药,Cancer Letters

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通过 STAT3/CD47-SIRPα 轴对 TAM 进行重编程可促进肺癌对 EGFR-TKI 的获得性耐药
Cancer Letters ( IF 9.1 ) Pub Date : 2023-05-04 , DOI: 10.1016/j.canlet.2023.216205
Jiaye Lu ₁ , Jingwei Li ₁ , Ziyou Lin ₁ , Huaxuan Li ₁ , Linlin Lou ₁ , Wen Ding ₁ , Shumin Ouyang ₁ , Yonghui Wu ₂ , Yuanzhen Wen ₃ , Xiaobing Chen ₃ , Peibin Yue ₄ , Yuanxiang Wang ₁ , Peiqing Liu ₁ , Jinjian Lu ₅ , Jian Zhang ₂ , Weineng Feng ₆ , Xiaolei Zhang ₁

Affiliation

肿瘤微环境（TME）和癌细胞之间的串扰在表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）获得性耐药中发挥着重要作用。肿瘤相关巨噬细胞 (TAM)（TME 的主要组成部分）在获得性耐药中的作用仍不清楚。在这项研究中，在吉非替尼耐药的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吞噬作用的减少。TKI耐药肺癌细胞中CD47表达上调，M2型巨噬细胞极化和癌细胞逃避巨噬细胞吞噬作用增强。TKI 抗性细胞的培养基导致 TAM 的代谢重编程。STAT3 与 TKI 耐药肺癌细胞中的 CD47 表达相关。STAT3 的遗传和药理学抑制增强了 TAM 的吞噬活性，并通过抑制共培养系统中的 CD47-SIRPα 信号轴和 M2 极化来减轻对 EGFR-TKI 的获得性耐药。此外，STAT3通过与CD47基因内含子中的共有DNA反应元件结合来转录调节CD47表达。此外，吉非替尼与STAT3抑制剂和抗CD47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。总的来说，我们的研究揭示了 TAM 重编程和 CD47-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中对 EGFR-TKI 的获得性耐药。

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

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.

更新日期：2023-05-04

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