Medical Oncology Department, Hospital del Mar - CIBERONC, Barcelona, Spain; IMIM (Instituto Hospital del Mar de Investigaciones Médicas), Barcelona, Spain.
Pathology Department, Hospital del Mar, Barcelona, Spain.
Lung Cancer. 2023 Jul;181:107257. doi: 10.1016/j.lungcan.2023.107257. Epub 2023 May 20.
Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery.
A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes.
We found increased levels of T cell markers (CD3, CD4, CD8 cells), functional immune markers (FOXP3 cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68 cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3, CD8 cells), regulatory T cells (FOXP3 cells) and macrophages (CD68 cells) was observed in the CD103/PD-L1 group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103 immune cells was associated with improved OS (p = 0.009).
TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.
新辅助和辅助免疫检查点阻断（ICB）最近已成为可切除非小细胞肺癌（NSCLC）的标准治疗方法。然而，告知患者哪些患者受益于这种方法的生物标志物在很大程度上仍然未知。在这里，我们研究了接受 upfront 手术的早期 NSCLC 患者的肿瘤免疫微环境（TIME）。
总共纳入了 185 名在 2006 年至 2018 年期间在 Hospital del Mar 接受 upfront 手术治疗的早期 NSCLC 治疗初治患者。包括 124 例肺腺癌（LUAD）和 61 例鳞状细胞癌（LUSC）的组织微阵列。使用数字图像分析（QuPath 软件）评估 CD3、CD4、CD8、CD68、CD80、CD103、FOXP3、PD-1、PD-L1、PD-L2 和 HLA 类 II 的免疫组化。根据肿瘤细胞（<1%或≥1%）和肿瘤驻留记忆（CD103）免疫细胞中 PD-L1 的表达，将 TIME 分为四组（使用中位数作为截止值）。我们探讨了不同 TIME 维度与患者临床病理特征和结局之间的关联。
与 LUSC 相比，我们发现 LUAD 中 T 细胞标志物（CD3、CD4、CD8 细胞）、功能免疫标志物（FOXP3 细胞）以及 HLA-II 肿瘤膜表达水平更高（所有 p<0.05）。相比之下，LUSC 显示肿瘤内巨噬细胞（CD68 细胞）的百分比更高，以及 PD-L1 和 PD-L2 肿瘤膜表达更高（所有 p<0.05）。非监督分析揭示了三种不同的肿瘤亚群，其特征是 PD-L1、PD-L2 和 HLA-II 的肿瘤膜表达。在 CD103/PD-L1 组中观察到 T 细胞（CD3、CD8 细胞）、调节性 T 细胞（FOXP3 细胞）和巨噬细胞（CD68 细胞）的浸润增加（所有 p<0.05）。多变量分析显示，CD103 免疫细胞浸润与 OS 改善相关（p=0.009）。
切除 NSCLC 中的 TIME 分析强调了组织学、PD-L1 表达和分子亚群的差异。使用 IHC 的生物标志物研究可能有助于为早期 NSCLC 患者量身定制辅助治疗。
