Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients’ prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8+ T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.

中文翻译：

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靶向CXCR2抑制肺癌进展促进顺铂治疗效果

化疗药物的耐药性和严重的副作用导致肺癌患者的生存率不令人满意。CXCLs/CXCR2 轴在包括肺癌在内的癌症进展中起重要作用。然而，靶向CXCR2的具体抗癌机制仍不清楚。对临床肺腺癌和肺鳞癌患者的肿瘤组织微阵列进行CXCR2的免疫组织化学分析。采用CCK8试验、TUNEL免疫荧光染色、PI-Annexin V染色、β-半乳糖苷酶染色、Western blot等方法在体外验证CXCR2的作用。应用尾静脉和皮下注射动物模型研究靶向CXCR2的治疗作用。流式细胞术、qRT-PCR、酶联免疫吸附试验（ELISA）、并进行免疫组织化学分析以进行进一步的机制研究。CXCR2在人肺癌基质和肿瘤细胞中的表达均升高，这与患者的预后有关。CXCR2 的抑制促进了肺癌细胞的凋亡、衰老、上皮间质转化 (EMT) 和抗增殖。体内研究表明，肿瘤相关中性粒细胞（TANs）显着浸润到小鼠模型的肿瘤组织中，上调CXCLs/CXCR2信号和抑制分子，包括Arg-1和TGF-β。SB225002 是一种选择性 CXCR2 抑制剂，显示出良好的治疗效果，通过促进 CD8+ T 细胞活化显着减少中性粒细胞的浸润并增强抗肿瘤 T 细胞活性。同时，CXCR2 的阻断可以通过调节中性粒细胞浸润来增强顺铂的治疗效果。我们的发现证实了靶向 CXCR2 在肺癌中的治疗效果，并揭示了 CXCR2 拮抗剂对化疗药物敏感性增加的潜在机制。