Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Berry Oncology Corporation, Fuzhou, China; Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, China.
Lung Cancer. 2024 Sep;195:107933. doi: 10.1016/j.lungcan.2024.107933. Epub 2024 Aug 22.
Non-small cell lung cancer (NSCLC) patients with exon 20 insertion mutations (ex20ins) of the epidermal growth factor receptor (EGFR) were resistant to monotherapy of immune checkpoint inhibitor (ICI). However, recent reports have shown that the combination of ICI and chemotherapy (ICI-combined regimen) exhibited certain efficacy for NSCLC with EGFR ex20ins. The mechanisms behind this phenomenon have not been thoroughly clarified. Hence, we conducted this study tofind correlations between the tumor immune microenvironment of EGFR ex20ins and the efficacy of ICI-combined regimen.
We performed single-cell transcriptome sequencing and multiplex immunofluorescence staining (mIF) to investigate the immune microenvironment of NSCLC patients with EGFR ex20ins, L858R, and EGFR wild-type. We analyzed 15 treatment-naïve NSCLC samples utilizing single-cell RNA sequencing (scRNA-seq). Another 30 cases of EGFR L858R and 4 cases of wild-type were recruited to compare the immune microenvironment with that of EGFR ex20ins (28 cases) by mIF.
We observed that cell components, function and interactions varied between EGFR ex20ins, L858R, and wild-type NSCLC.We discovered similar T cell and CD8+ T cell distributions among groups but found noninferior or even better T cell activation in ex20ins patients. Infiltrating CD8+ FOXP3- T cells were significantly lower in the tumor region of EGFR ex20ins compared to wild-type. T cells from the ex20ins group had a greater tendency to promote cancer cell inflammation and epithelial-mesenchymal transition (EMT) compared to wild-type group. For macrophages, there were more M2-like macrophages in ex20ins patients. M1-like macrophages in ex20ins group produced fewer antitumor cytokines than in other groups.
The immune microenvironment of EGFR ex20ins is more suppressive than that of L858R and wild-type, suggesting that ICI monotherapy may not be sufficient for these patients. ICI-combined regimen might be a treatment option for EGFR ex20ins due to tumor-promoting inflammation and noninferior T cell functions in the immune microenvironment.
表皮生长因子受体（EGFR）exon20 插入突变（ex20ins）的非小细胞肺癌（NSCLC）患者对免疫检查点抑制剂（ICI）单药治疗耐药。然而，最近的报告显示，ICI 联合化疗（ICI 联合治疗方案）对 EGFR ex20ins 型 NSCLC 具有一定疗效。这种现象背后的机制尚未得到彻底阐明。因此，我们进行了这项研究，以寻找 EGFR ex20ins 与 ICI 联合治疗方案疗效之间的肿瘤免疫微环境相关性。
我们进行了单细胞转录组测序和多重免疫荧光染色（mIF），以研究 EGFR ex20ins、L858R 和 EGFR 野生型 NSCLC 患者的免疫微环境。我们利用单细胞 RNA 测序（scRNA-seq）分析了 15 例未经治疗的 NSCLC 样本。另外招募了 30 例 EGFR L858R 和 4 例野生型病例，通过 mIF 与 EGFR ex20ins（28 例）比较免疫微环境。
我们观察到 EGFR ex20ins、L858R 和野生型 NSCLC 之间细胞成分、功能和相互作用存在差异。我们发现各组之间 T 细胞和 CD8+T 细胞分布相似，但在 ex20ins 患者中发现了非劣效或甚至更好的 T 细胞激活。与野生型相比，EGFR ex20ins 肿瘤区域浸润的 CD8+FOXP3-T 细胞明显减少。与野生型组相比，ex20ins 组的 T 细胞更倾向于促进癌细胞炎症和上皮-间充质转化（EMT）。对于巨噬细胞，ex20ins 患者中有更多的 M2 样巨噬细胞。ex20ins 组 M1 样巨噬细胞产生的抗肿瘤细胞因子比其他组少。
EGFR ex20ins 的免疫微环境比 L858R 和野生型更具抑制性，提示 ICI 单药治疗可能对这些患者不足。由于肿瘤促进炎症和免疫微环境中 T 细胞功能非劣效，ICI 联合治疗可能是 EGFR ex20ins 的一种治疗选择。
