College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310053, China; Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou 310053, China.
Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou 310053, China.
Biomed Pharmacother. 2024 Apr;173:116306. doi: 10.1016/j.biopha.2024.116306. Epub 2024 Feb 23.
Clinical resistance to EGFR tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) remains a significant challenge. Recent studies have indicated that the number of myeloid-derived suppressor cells (MDSCs) increases following gefitinib treatment, correlating with a poor patient response in NSCLC. Our study revealed that gefitinib treatment stimulates the production of CCL2, which subsequently enhances monocyte (M)-MDSC migration to tumor sites. Chidamide, a selective inhibitor of the histone deacetylase subtype, counteracted the gefitinib-induced increase in CCL2 levels in tumor cells. Additionally, chidamide down-regulated the expression of CCR2 in M-MDSCs, inhibiting their migration. Furthermore, chidamide attenuated the immunosuppressive function of M-MDSCs both alone and in combination with gefitinib. Chidamide also alleviated tumor immunosuppression by reducing the number of M-MDSCs in LLC-bearing mice, thereby enhancing the antitumor efficacy of gefitinib. In conclusion, our findings suggest that chidamide can improve gefitinib treatment outcomes, indicating that MDSCs are promising targets in NSCLC.
非小细胞肺癌（NSCLC）中表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的临床耐药仍然是一个重大挑战。最近的研究表明，吉非替尼治疗后髓系来源的抑制细胞（MDSCs）数量增加，与 NSCLC 患者的不良反应相关。我们的研究表明，吉非替尼治疗刺激 CCL2 的产生，随后增强单核细胞（M）-MDSC 向肿瘤部位的迁移。西达本胺是组蛋白去乙酰化酶亚型的选择性抑制剂，可拮抗吉非替尼诱导的肿瘤细胞中 CCL2 水平的增加。此外，西达本胺下调了 M-MDSC 中 CCR2 的表达，抑制其迁移。此外，西达本胺单独或与吉非替尼联合使用均可减弱 M-MDSC 的免疫抑制功能。西达本胺还通过减少荷瘤小鼠中 M-MDSC 的数量减轻肿瘤免疫抑制，从而增强吉非替尼的抗肿瘤疗效。总之，我们的研究结果表明，西达本胺可以改善吉非替尼的治疗效果，表明 MDSCs 是 NSCLC 的有前途的靶点。
