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

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2024-06-07 DOI:10.1002/jgm.3694

Xinyun Fang, Dianke Li, Shiyue Wan, Junjie Hu, Peng Zhang, Dai Jie, Linsong Chen, Gening Jiang, Nan Song

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引用次数: 0

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.

查看原文本刊更多论文

通过单细胞转录组分析了解肺腺癌和鳞癌肿瘤微环境的异质性：对不同免疫疗法结果的影响

背景：免疫检查点阻断已成为治疗非小细胞肺癌（NSCLC）的关键策略。然而，肺腺癌（LUAD）和肺鳞癌（LUSC）这两种主要的非小细胞肺癌亚型之间的免疫治疗结果存在显著差异。这种差异可能源于肿瘤免疫微环境在转录组水平上的异质性：本研究通过单细胞RNA测序对38例NSCLC患者的转录组特征进行综合分析，发现LUAD和LUSC之间存在不同的肿瘤微环境（TME），相关结果在新辅助免疫疗法患者的批量转录组和多重免疫荧光（mIF）验证队列中得到进一步证实：结果：与LUSC相比，LUAD表现出更活跃的免疫微环境。这包括癌细胞中 HLA I/II 的高表达、树突状细胞抗原呈递潜能的增强以及 T/NK 细胞细胞毒性活性的增强。在 LUSC 中，癌细胞高表达属于醛酮还原酶、谷胱甘肽 S 转移酶和醛脱氢酶家族的基因，这与本中心验证队列中的免疫疗法结果呈负相关。进一步分析发现，LUSC 中浸润的癌相关成纤维细胞（CAFs）增加，这在癌症基因组图谱队列中得到了证实。多重 mIF 显示，在主要病理反应（MPR）患者中，ADH1B+ CAFs 的浸润相应增加，而在非主要病理反应患者中，FAP+ CAFs 的存在率较高。此外，在 LUSC 中还发现了免疫抑制性细胞外基质重塑的上调：这些综合分析加深了人们对 LUAD 和 LUSC TME 差异的理解，为选择患者和制定亚型特异性治疗策略提供了启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.