血浆细胞外囊泡长RNA谱分析鉴定肺鳞状细胞癌免疫化疗疗效的预测标志物

Plasma extracellular vesicle long RNA profiling identifies a predictive signature for immunochemotherapy efficacy in lung squamous cell carcinoma

Frontiers in Immunology

影响因子:5.9

分区:医学2区 / 免疫学2区

发表日期:2024

作者: Xin Zhang, Jiatao Liao, Wenyue Yang, Qiaojuan Li, Zhen Wang, Hui Yu, Xianghua Wu, Huijie Wang, Si Sun, Xinmin Zhao, Zhihuang Hu, Jialei Wang

DOI: 10.3389/fimmu.2024.1421604

摘要

免疫检查点抑制剂（ICIs）的引入标志着肺鳞状细胞癌（LUSC）治疗范式的转变，强调了迫切需要可靠的分子生物标志物以预测治疗效果。本研究旨在通过血浆细胞外囊泡（EV）衍生长RNA（exLRs）鉴定免疫化疗疗效的潜在生物标志物。我们招募了78例接受一线免疫化疗的晚期LUSC患者，收集血浆样本并进行exLR测序，以建立基线表达谱。对42例患者进行了回顾性分析，筛选差异表达的exLRs，并利用定量逆转录PCR（qRT-PCR）对 Top差异表达的exLRs进行验证。采用单变量Cox分析评估这些exLRs的预后意义。基于分析结果，我们建立了一个预测标志物（p-签名）。在42例患者的回顾性分析中，筛选出460个差异表达的exLRs，其中与非反应者相关的信号通路主要涉及白细胞迁移。单变量Cox分析发现有45个exLRs具有预后相关性。验证中，前6个编码蛋白的exLRs（包括CXCL8、SSH3和SDHAF1）在反应者与非反应者之间表现出显著差异。p-签名由这三个exLRs组成，在区分反应者与非反应者方面表现出较高的准确性，在回顾性队列中的曲线下面积（AUC）为0.904，在前瞻性队列中为0.812。本研究显示血浆exLR谱具有预测LUSC治疗效果的潜力。有趣的是，较低的p-签名评分与活化的CD4+和CD8+ T细胞丰度增加相关，提示免疫环境更为活跃。这些发现表明，p-签名可能成为指导LUSC个性化治疗策略的重要工具。

Abstract

The introduction of Immune Checkpoint Inhibitors (ICIs) has marked a paradigm shift in treating Lung Squamous Cell Carcinoma (LUSC), emphasizing the urgent need for precise molecular biomarkers to reliably forecast therapeutic efficacy. This study aims to identify potential biomarkers for immunochemotherapy efficacy by focusing on plasma extracellular vesicle (EV)-derived long RNAs (exLRs).We enrolled 78 advanced LUSC patients undergoing first-line immunochemotherapy. Plasma samples were collected, and exLR sequencing was conducted to establish baseline profiles. A retrospective analysis was performed on 42 patients to identify differentially expressed exLRs. Further validation of the top differentially expressed exLRs was conducted using quantitative reverse transcription PCR (qRT-PCR). Univariate Cox analysis was applied to determine the prognostic significance of these exLRs. Based on these findings, we developed a predictive signature (p-Signature).In the retrospective analysis of 42 patients, we identified 460 differentially expressed exLRs, with pathways related to leukocyte migration notably enriched among non-responders. Univariate Cox analysis revealed 45 exLRs with prognostic significance. The top 6 protein-coding exLRs were validated using qRT-PCR, identifying CXCL8, SSH3, and SDHAF1 as differentially expressed between responders and non-responders. The p-Signature, comprising these three exLRs, demonstrated high accuracy in distinguishing responders from non-responders, with an Area Under the Curve (AUC) of 0.904 in the retrospective cohort and 0.812 in the prospective cohort.This study highlighted the potential of plasma exLR profiles in predicting LUSC treatment efficacy. Intriguingly, lower p-Signature scores were associated with increased abundance of activated CD4+ and CD8+ T cells, indicating a more robust immune environment. These findings suggest that the p-Signature could serve as a valuable tool in guiding personalized and effective therapeutic strategies for LUSC.