Zhang Yanhui, Cheng Runfen, Ding Tingting, Wu Jianghua
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
Transl Lung Cancer Res. 2024 Dec 31;13(12):3590-3602. doi: 10.21037/tlcr-24-735. Epub 2024 Dec 27.
Differences in the immune microenvironment and responses to immunotherapy may exist between primary non-small cell lung cancer (NSCLC) and brain metastases (BMs). This study aimed to investigate discrepancies in programmed death-ligand 1 (PD-L1) expression, tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLS), and tumor mutational burden (TMB) between matched BMs and primary tumors (PTs) in NSCLC.
Twenty-six pairs of surgically resected BMs and corresponding PTs from NSCLC patients were collected. PD-L1 expression and TILs, including CD8, CD3, CD4, CD20, CD68, and CD21, were analyzed using immunohistochemistry (IHC) and quantitatively assessed through digital image analysis. Whole-exome sequencing (WES) was performed to investigate genomic discrepancies and variations in TMB.
The density of PD-L1 cells did not differ significantly between matched PTs and BMs (P>0.99). However, BMs exhibited a higher tumor proportion score (TPS) compared to PTs (mean TPS: 31.92% 25.96%, P=0.049), with moderate agreement in categorized TPS (κ=0.653). Analysis of TILs revealed a significant reduction in CD3 T cells (P<0.001), CD8 cytotoxic T cells (P<0.001), CD20 B cells (P<0.001), and CD68 macrophages (P=0.02) in BMs compared to PTs. BMs also exhibited a loss of TLS, with no presence of mature TLS marked by CD21 expression. The number of non-synonymous mutations was generally higher in BMs than in PTs, with only 34.69% of mutations shared between paired PTs and BMs. TMB was slightly increased in BMs (mean TMB: 34.2 mutations/Mb in BMs 26.8 mutations/Mb in PTs; P=0.30). Additionally, the log-rank test indicated that a higher density of CD20 B cells in BMs was significantly associated with better overall survival (P=0.007).
Compared to primary NSCLC tumors, matched BMs show an increase in TPS of PD-L1 expression and TMB, but a significant reduction in TILs and loss of mature TLS, suggesting an immune-suppressive microenvironment in BMs. The infiltration of CD20 B cells may serve as a potential prognostic biomarker in NSCLC with BMs.
原发性非小细胞肺癌（NSCLC）与脑转移瘤（BMs）之间可能存在免疫微环境及免疫治疗反应的差异。本研究旨在调查NSCLC中配对的BMs与原发性肿瘤（PTs）之间程序性死亡配体1（PD-L1）表达、肿瘤浸润淋巴细胞（TILs）、三级淋巴结构（TLS）和肿瘤突变负荷（TMB）的差异。
收集26例NSCLC患者手术切除的BMs及其相应的PTs。采用免疫组织化学（IHC）分析PD-L1表达及TILs，包括CD8、CD3、CD4、CD20、CD68和CD21，并通过数字图像分析进行定量评估。进行全外显子测序（WES）以研究基因组差异和TMB的变化。
配对的PTs和BMs之间PD-L1细胞密度无显著差异（P>0.99）。然而，与PTs相比，BMs的肿瘤比例评分（TPS）更高（平均TPS：31.92%±25.96%，P=0.049），分类TPS具有中度一致性（κ=0.653）。TILs分析显示，与PTs相比，BMs中的CD3 T细胞（P<0.001）、CD8细胞毒性T细胞（P<0.001）、CD20 B细胞（P<0.001）和CD68巨噬细胞（P=0.02）显著减少。BMs还表现出TLS缺失，不存在以CD21表达为特征的成熟TLS。BMs中的非同义突变数量通常高于PTs，配对的PTs和BMs之间只有34.69%的突变相同。BMs中的TMB略有增加（平均TMB：BMs中为34.2个突变/Mb，PTs中为26.8个突变/Mb；P=0.30）。此外，对数秩检验表明，BMs中较高密度的CD20 B细胞与更好的总生存期显著相关（P=0.007）。
与原发性NSCLC肿瘤相比，配对的BMs显示PD-L1表达的TPS和TMB增加，但TILs显著减少且成熟TLS缺失，提示BMs中存在免疫抑制微环境。CD20 B细胞的浸润可能是NSCLC伴BMs的潜在预后生物标志物。
