{"title":"PD-L1表达、淋巴细胞浸润和肿瘤突变负担在非小细胞肺癌和匹配的脑转移中的差异","authors":"Yanhui Zhang, Runfen Cheng, Tingting Ding, Jianghua Wu","doi":"10.21037/tlcr-24-735","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The density of PD-L1<sup>+</sup> 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% <i>vs.</i> 25.96%, P=0.049), with moderate agreement in categorized TPS (κ=0.653). Analysis of TILs revealed a significant reduction in CD3<sup>+</sup> T cells (P<0.001), CD8<sup>+</sup> cytotoxic T cells (P<0.001), CD20<sup>+</sup> B cells (P<0.001), and CD68<sup>+</sup> 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 <i>vs.</i> 26.8 mutations/Mb in PTs; P=0.30). Additionally, the log-rank test indicated that a higher density of CD20<sup>+</sup> B cells in BMs was significantly associated with better overall survival (P=0.007).</p><p><strong>Conclusions: </strong>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<sup>+</sup> B cells may serve as a potential prognostic biomarker in NSCLC with BMs.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3590-3602"},"PeriodicalIF":4.0000,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736585/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discrepancies in PD-L1 expression, lymphocyte infiltration, and tumor mutational burden in non-small cell lung cancer and matched brain metastases.\",\"authors\":\"Yanhui Zhang, Runfen Cheng, Tingting Ding, Jianghua Wu\",\"doi\":\"10.21037/tlcr-24-735\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The density of PD-L1<sup>+</sup> 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% <i>vs.</i> 25.96%, P=0.049), with moderate agreement in categorized TPS (κ=0.653). Analysis of TILs revealed a significant reduction in CD3<sup>+</sup> T cells (P<0.001), CD8<sup>+</sup> cytotoxic T cells (P<0.001), CD20<sup>+</sup> B cells (P<0.001), and CD68<sup>+</sup> 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 <i>vs.</i> 26.8 mutations/Mb in PTs; P=0.30). Additionally, the log-rank test indicated that a higher density of CD20<sup>+</sup> B cells in BMs was significantly associated with better overall survival (P=0.007).</p><p><strong>Conclusions: </strong>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<sup>+</sup> B cells may serve as a potential prognostic biomarker in NSCLC with BMs.</p>\",\"PeriodicalId\":23271,\"journal\":{\"name\":\"Translational lung cancer research\",\"volume\":\"13 12\",\"pages\":\"3590-3602\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-12-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736585/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Translational lung cancer research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.21037/tlcr-24-735\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational lung cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21037/tlcr-24-735","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/27 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：原发性非小细胞肺癌（NSCLC）和脑转移瘤（BMs）在免疫微环境和免疫治疗反应方面可能存在差异。本研究旨在探讨非小细胞肺癌匹配脑转移瘤和原发肿瘤（PTs）在程序性死亡配体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）方面的差异。方法：收集非小细胞肺癌患者手术切除的脑转移灶及相应的PTs 26对。采用免疫组化（IHC）分析PD-L1表达和TILs，包括CD8、CD3、CD4、CD20、CD68和CD21，并通过数字图像分析定量评估。采用全外显子组测序（WES）研究TMB的基因组差异和变异。结果：PD-L1+细胞密度在匹配的PTs和脑转移瘤之间无显著差异（P < 0.99）。然而，脑转移患者的肿瘤比例评分（TPS）高于PTs（平均TPS: 31.92% vs. 25.96%， P=0.049），分类TPS的一致性中等（κ=0.653）。TILs分析显示，与PTs相比，脑转移灶中CD3+ T细胞（P+细胞毒性T细胞）（P+ B细胞）（P+巨噬细胞）显著减少（P=0.02）。脑转移瘤也表现出TLS缺失，不存在以CD21表达为标志的成熟TLS。脑转移患者的非同义突变数量普遍高于脑转移患者，只有34.69%的突变在配对的PTs和脑转移患者之间共享。脑转移患者的TMB略有增加(脑转移患者的平均TMB: 34.2个突变/Mb vs. PTs的26.8个突变/Mb；P = 0.30)。此外，log-rank检验表明，脑转移瘤中CD20+ B细胞密度越高，总生存率越高（P=0.007）。结论：与原发性NSCLC肿瘤相比，匹配的脑转移灶PD-L1表达的TPS和TMB增加，但TILs显著降低，成熟TLS缺失，提示脑转移灶存在免疫抑制微环境。CD20+ B细胞的浸润可能是伴有脑转移的非小细胞肺癌的潜在预后生物标志物。
Discrepancies in PD-L1 expression, lymphocyte infiltration, and tumor mutational burden in non-small cell lung cancer and matched brain metastases.
Background: 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.
Methods: 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.
Results: 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% vs. 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 vs. 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).
Conclusions: 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.
期刊介绍：
Translational Lung Cancer Research(TLCR, Transl Lung Cancer Res, Print ISSN 2218-6751; Online ISSN 2226-4477) is an international, peer-reviewed, open-access journal, which was founded in March 2012. TLCR is indexed by PubMed/PubMed Central and the Chemical Abstracts Service (CAS) Databases. It is published quarterly the first year, and published bimonthly since February 2013. It provides practical up-to-date information on prevention, early detection, diagnosis, and treatment of lung cancer. Specific areas of its interest include, but not limited to, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to lung cancer.
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