摘要
目的探讨非小细胞肺癌(NSCLC)脑转移患者的临床和免疫微环境特征及其对患者预后的影响。方法回顾性分析2020年1月至2022年12月重庆大学附属肿瘤医院神经肿瘤科手术治疗并经病理学证实的77例成人NSCLC脑转移患者的临床资料。采用多重荧光免疫组织化学(mIHC)技术检测肿瘤实质和间质中CD68+肿瘤相关巨噬细胞(TAMs)、CD8+T细胞、CD4+T细胞、程序性死亡受体1(PD1)+T细胞以及CD4+和PD1+双阳性T细胞的占比,并采用X-tile软件分析确定连续变量的最佳截断值,据此将上述细胞定义为高占比和低占比,将其转化为分类变量。采用单因素和多因素Cox比例风险回归模型筛选对患者总生存期(OS)有影响的临床及免疫微环境因素。根据筛选出的影响因素分别绘制Kaplan-Meier生存曲线,组间比较采用log-rank检验。结果77例患者中,转移瘤位于小脑幕上59例(76.6%),小脑幕下18例(23.4%);病理学类型以腺癌为主[63例(81.8%)],其次是鳞癌[12例(15.6%)],肉瘤样癌较罕见[2例(2.6%)]。mIHC结果显示,CD68+TAMs、CD8+T细胞和CD4+T细胞在肿瘤间质中的占比高于肿瘤实质,差异均具有统计学意义(均P<0.001);而PD1+T细胞在肿瘤实质中的占比高于肿瘤间质,差异有统计学意义(P<0.001)。CD4+和PD1+双阳性T细胞在肿瘤实质与间质中占比的差异无统计学意义(P=0.360)。所有患者的随访时间为(18±1)个月(2~45个月);1年和2年生存率分别为72.7%(56/77)和28.6%(22/77)。多因素Cox比例风险回归模型分析显示,病理学类型为鳞癌(HR=0.06,95%CI:0.01~0.38)、术后接受综合治疗(包括化疗、放疗、靶向治疗或免疫治疗中至少1种)(HR=0.13,95%CI:0.06~0.29),以及肿瘤实质CD4+和PD1+双阳性T细胞占比高(HR=0.13,95%CI:0.04~0.41)均是患者OS的保护性因素(均P<0.001)。Kaplan-Meier生存曲线分析显示,鳞癌和腺癌患者的OS较肉瘤样癌患者长(中位值分别为未达到、27、3个月,P<0.001);接受术后综合治疗的患者OS较未接受综合治疗者长(中位值分别为37、8个月,P<0.001);肿瘤实质中CD4+和PD1+双阳性T细胞占比高的患者OS较占比低的患者长(中位值分别为未达到、21个月,P=0.001)。结论NSCLC脑转移的免疫微环境呈现明显的空间异质性。肿瘤病理学类型和术后是否接受综合治疗均影响患者预后。肿瘤实质CD4+和PD1+双阳性T细胞占比可能是预测患者预后的重要指标。
Objective To investigate the clinico-immunological microenvironment characteristics of non-small cell lung cancer(NSCLC)brain metastases and their impact on the patient prognosis.Methods Clinical data of 77 adult NSCLC brain metastasis patients who underwent surgical treatment and were pathologically confirmed at the Department of Neuro-Oncology of Chongqing University Cancer Hospital from January 2020 to December 2022 were retrospectively analyzed.Multiplex immunohistochemistry(mIHC)was used to detect the proportions of CD68+tumor-associated macrophages(TAMs),CD8+T cells,CD4+T cells,programmed cell death protein 1(PD1)+T cells,and CD4+PD1+double-positive T cells in tumor parenchyma and stroma.The X-tile software was employed to determine the optimal cutoff values for continuous variables,converting them into categorical variables.Univariate and multivariate Cox proportional hazards regression models were used to evaluate the effects of clinical and immune microenvironment factors on the overall survival(OS)of patients.Kaplan-Meier survival curves were plotted based on identified influential factors,with log-rank tests performed for between-group comparisons.Results Among the 77 patients,59(76.6%)had metastases in supratentorial location and 18(23.4%)in infratentorial location.The predominant pathological type was adenocarcinoma(63 cases,81.8%),followed by squamous cell carcinoma(12 cases,15.6%),while sarcomatoid carcinoma was rare(2 cases,2.6%).The mIHC results showed that the proportions of CD68+TAMs,CD8+T cells,and CD4+T cells in the tumor stroma were higher than those in the tumor parenchyma,with statistically significant differences(all P<0.001).However,the proportion of PD1+T cells in the tumor parenchyma was higher than that in the stroma(P<0.001).There was no statistically significant difference in the proportion of CD4+PD1+double-positive T cells between tumor parenchyma and stroma(P=0.360).The follow-up time for all patients was 18±1 months(range:2-45 months),with 1-year and 2-year survival rates of 72.7%(56/77)and 28.6%(22/77),respectively.Multivariate Cox proportional hazards regression models analysis showed that squamous cell carcinoma pathology(HR=0.06,95%CI:0.01-0.38),postoperative comprehensive treatment(including at least one of chemotherapy,radiotherapy,targeted therapy,or immunotherapy)(HR=0.13,95%CI:0.06-0.29),and a higher proportion of CD4+PD1+double-positive T cells in the tumor parenchyma(HR=0.13,95%CI:0.04-0.41)were all protective factors for OS(all P<0.001).Kaplan-Meier survival curve analysis showed that patients with squamous and adenocarcinoma cell carcinoma had longer OS than those with sarcomatoid carcinoma(median values:not achieved,27 and 3 months respectively,P<0.001);patients who received postoperative comprehensive treatment had longer OS than those who did not(median values:37 and 8 months respectively,P<0.001);and patients with a higher proportion of CD4+PD1+double-positive T cells in the tumor parenchyma had longer OS than those with a lower proportion(median values:not achieved and 21 months respectively,P=0.001).Conclusion sThe immune microenvironment of NSCLC brain metastases exhibits significant spatial heterogeneity.Both patient's tumour pathological type and whether or not received postoperative comprehensive treatment affect the patient's prognosis.The proportion of CD4+PD1+double-positive T cells in the tumor parenchyma may be an important indicator for predicting patient prognosis.
作者
程兴
黄加尚
王淼
李立东
向廷秀
杨海峰
Cheng Xing;Huang Jiashang;Wang Miao;Li Lidong;Xiang Tingxiu;Yang Haifeng(Department of Neuro-oncology,Chongqing University Cancer Hospital,Chongqing 400030,China;Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment,Chongqing University Cancer Hospital,Chongqing 400030,China)
出处
《中华神经外科杂志》
北大核心
2025年第6期569-576,共8页
Chinese Journal of Neurosurgery
基金
国家自然科学基金(82172619)
重庆市自然科学基金(2024MSXM1129)
重庆市沙坪坝区科卫联合项目(2023SQKWLH004)。
关键词
脑肿瘤
肿瘤转移
癌
非小细胞肺
肿瘤微环境
预后
影响因素分析
Brain neoplasms
Neoplasm metastasis
Carcinoma,non-small-cell lung
Tumor microenvironment
Prognosis
Root cause analysis
作者简介
通信作者:杨海峰,Email:yanghaifeng@cqu.edu.cn。
