Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

肿瘤微环境 腺癌 免疫疗法 癌症研究 生物 肺癌 免疫检查点 免疫系统 转录组 细胞毒性T细胞 癌症 肿瘤科 免疫学 医学 内科学 基因表达 基因 体外 生物化学
作者
Xinyun Fang,Dianke Li,Shiyue Wan,Junjie Hu,Peng Zhang,Jie Dai,Linsong Chen,Gening Jiang,Nan Song
出处
期刊:Journal of Gene Medicine [Wiley]
卷期号:26 (6) 被引量:1
标识
DOI:10.1002/jgm.3694
摘要

Abstract Background Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non‐small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. Methods By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single‐cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. Results LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo‐keto reductases, glutathione S ‐transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer‐associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non‐MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. Conclusions These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype‐specific treatment strategies.
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