背景:探讨驱动阴性晚期或转移性非小细胞肺癌(NSCLC)患者免疫微环境特征的性别异质性及其对一线PD-1阻断加化疗反应的影响。
方法:共439例接受一线PD-1阻断联合化疗或化疗的晚期NSCLC患者。使用Kaplan-Meier曲线确定女性和男性患者之间临床结果的差异。比较两组的新抗原负荷和5种免疫微环境标志物PD-L1、CD4、CD8、FOXP3和CD68的表达。
结果:在175名符合条件的患者中,89人接受PD-1阻断加化疗,86人接受一线化疗。45名女性(25.7%)和130名男性(74.3%)。接受一线PD-1阻断联合化疗的女性患者ORR显著改善(85.2%vs.53.2%;p=0.009),PFS(23.7vs.7.3个月;p=0.013),和操作系统(46.2与20.0个月;p=0.004)比男性高。化疗组女性和男性的治疗结果相似。多因素分析显示,性别是PD-1阻断联合化疗患者的独立预后因素。尽管女性患者的肿瘤突变和新抗原负担明显低于男性,女性患者治疗前肿瘤组织中CD4、CD4/FOXP3和CD4/FOXP3/PD-L1表达水平明显高于男性患者。
结论:女性未经治疗的晚期或转移性NSCLC患者将比男性从PD-1阻断联合化疗中获得更大的益处。肿瘤免疫微环境特征之间异质性的生物学意义有待进一步研究。
BACKGROUND: To investigate the sex-based heterogeneity of immune microenvironmental feature and its impact on the response to first-line PD-1 blockade plus chemotherapy in patients with driver-negative advanced or metastatic non-small-cell lung cancer (NSCLC).
METHODS: A total of 439 patients with advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy or chemotherapy were identified. Differences in clinical outcomes between female and male patients were determined using Kaplan-Meier curves. Neoantigen burden and five immune microenvironmental markers expression including PD-L1, CD4, CD8, FOXP3, and CD68 were compared between two groups.
RESULTS: Of 175 eligible patients, 89 received PD-1 blockade plus chemotherapy and 86 received first-line chemotherapy. Forty five were women (25.7%) and 130 were men (74.3%). Female patients received first-line PD-1 blockade in combination with chemotherapy had dramatically better ORR (85.2% vs. 53.2%; p = 0.009), PFS (23.7 vs. 7.3 months; p = 0.013), and OS (46.2 vs. 20.0 months; p = 0.004) than males. Treatment outcomes were similar between females and males in chemotherapy group. Multivariate analyses showed that sex was the independent prognostic factor for patients received PD-1 blockade combined with chemotherapy. Although female patients had significantly lower tumor mutational and neoantigen burden than males, pretreatment tumor tissues of female patients had markedly higher CD4, CD4/FOXP3, and CD4/FOXP3/PD-L1 expression level than male patients.
CONCLUSIONS: Female patients with untreated advanced or metastatic NSCLC would derive a larger benefit from PD-1 blockade in combination with chemotherapy than males. The biological significances of heterogeneity of tumor immune microenvironmental features between them need further investigation.