驱动基因阴性晚期非小细胞肺癌脑转移免疫微环境及免疫治疗的研究进展

Progress in immune microenvironment and immunotherapy of driver gene negative advanced non-small cell lung cancer patients with brain metastases

远端转移是晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者难以避免的并发症,脑转移(brain metastases,BM)是此类患者最常见的转移部位之一。脑转移患者可能出现头痛、视物模糊、偏瘫、肢体麻木等症状,生存质量受到严重影响。脑转移患者通常预后较差,自然中位生存期仅有3个月左右。传统上,针对驱动基因阴性NSCLC脑转移的治疗策略有局部干预的外科手术、放射治疗及系统性干预的化疗等,而有明确基因突变如EGFR、ALK、ROS1等的患者可采用新一代靶向药物治疗,但两类患者颅内治疗疗效均欠佳。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的出现为晚期肺癌的治疗带来新希望,其在黑色素瘤及肺癌脑转移患者中观察到了一定疗效。脑转移瘤的血管与正常脑血管存在显著差异。不同于肺部原发病灶,脑转移瘤具有独特的肿瘤微环境、免疫细胞特征及血管结构,无论是免疫单药治疗还是免疫联合治疗对肺癌脑转移患者均有效。由于难以获得脑组织样本,免疫治疗的生物标志物的研究受到限制。除了肿瘤细胞程序性死亡-配体1(programmed cell death ligand-1,PD-L1)外,肿瘤突变负荷(tumor mutation burden,TMB)可能是预测免疫治疗疗效的潜在生物标志物。本文梳理脑部肿瘤的微环境特征,回顾ICIs治疗相关研究进展,拟为驱动基因阴性NSCLC脑转移患者的治疗提供参考。

Distant metastases are inevitable in patients with advanced non-small cell lung cancer(NSCLC),and the brain is one of the most common site of metastasis.Patients who suffer brain metastases(BM)may have headaches,blurred vision,hemiplegia,limb numbness,and other symptoms.Quality of life is severely impacted for these patients.Previous studies have shown that prognosis for patients with BM is usually very poor,and natural median survival time is only about 3 months.Traditional treatment strategies for driver-gene negative NSCLC patients with BM include local intervention surgery,radiotherapy,and systemic chemotherapy.New generation targeted drugs can be used for patients with gene mutations such as EGFR,ALK,and ROS1.However,the efficacy of both approaches has not been optimized in patients with BM.Immunotherapy based on immune checkpoint inhibitors(ICIs)has brought new hope to patients with advanced NSCLC.A large number of randomized clinical trials have shown that the application of ICIs on melanoma and NSCLC patients with BM can produce amazing anti-tumor effects compared with chemotherapy.Studies have confirmed that the vasculature in BM is significantly different from normal cerebral vasculature.BM also establish a unique tumor microenvironment,and unique immune cell components and functions.The characteristics of immune cells infiltrating metastases are different from those infiltrating primary lesions.In addition,several retrospective studies have found that either immune-monotherapy or combined immunotherapy is effective in lung cancer patients with BM.Research into predictive biomarkers for assessing the efficacy of immunotherapy is hampered by the difficulty of obtaining brain tissue samples.In addition to programmed cell death ligand-1(PD-L1)expression in tumor cells,tumor mutation burden(TMB)may be a potential biomarker to predict the efficacy of immunotherapy.This review focuses on tumor microenvironment of NSCLC metastases,and surveys progress in ICI therapies,to provide a reference for the treatment of NSCLC patients with BM.