探讨肠道微生物群与免疫检查点抑制剂在非小细胞肺癌治疗中的关系：从“肺与大肠相表里”理论中得到的启示。

OBJECTIVE: This study is aim to discern the Traditional Chinese Medicine (TCM) syndrome classifications relevant to immunotherapy sensitive in non-small cell lung cancer (NSCLC) patients, and to delineate intestinal microbiota biomarkers and impact that wield influence over the efficacy of NSCLC immunotherapy, grounded in the TCM theory of "lung and large intestine stand in exterior-interior relationship." METHODS: The study cohort consisted of patients with advanced NSCLC who received treatment at the Oncology Department of Chengdu Fifth People's Hospital. These patients were categorized into distinct TCM syndrome types and subsequently administered immune checkpoint inhibitors (ICIs), specifically PD-1 inhibitors. Stool specimens were collected from patients both prior to and following treatment. To scrutinize the differences in microbial gene sequences and species of the intestinal microbiota, 16S rRNA amplicon sequencing technology was employed. Additionally, peripheral blood samples were collected, and the analysis encompassed the assessment of T lymphocyte subsets and myeloid suppressor cell subsets via flow cytometry. Subsequently, alterations in the immune microenvironment pre- and post-treatment were thoroughly analyzed. RESULTS: The predominant clinical manifestations of advanced NSCLC patients encompassed spleen-lung Qi deficiency syndrome and Qi-Yin deficiency syndrome. Notably, the latter exhibited enhanced responsiveness to ICIs with a discernible amelioration of the immune microenvironment. Following ICIs treatment, significant variations in microbial abundance were identified among the three strains: Clostridia, Lachnospiraceae, and Lachnospirales, with a mutual dependency relationship. In the subset of patients manifesting positive PD-L1 expression and enduring therapeutic benefits, the study recorded marked increases in the ratios of CD3%, CD4%, and CD4/CD8 within the T lymphocyte subsets. Conversely, reductions were observed in the ratios of CD8%, Treg/CD4, M-MDSC/MDSC, and G-MDSC/MDSC. CONCLUSION: The strains Clostridia, Lachnospiraceae, and Lachnospirales emerge as potential biomarkers denoting the composition of the intestinal microbiota in the NSCLC therapy. The immunotherapy efficacy of ICIs markedly accentuates in patients displaying durable treatment benefits and those expressing positive PD-L1.

目的：本研究旨在识别与非小细胞肺癌（NSCLC）患者免疫治疗敏感相关的中医（TCM）证候分类，并描绘肠道微生物群生物标志物及其对 NSCLC 免疫治疗疗效的影响，基于“肺与大肠相表里”的 TCM 理论。

方法：研究队列包括在成都第五人民医院肿瘤科接受治疗的晚期 NSCLC 患者。这些患者被分为不同的 TCM 证候类型，随后接受免疫检查点抑制剂（ICIs），特别是 PD-1 抑制剂治疗。在治疗前后采集患者的粪便标本。为了研究肠道微生物群的微生物基因序列和物种差异，采用 16S rRNA 扩增子测序技术。此外，采集外周血样本，通过流式细胞术评估 T 淋巴细胞亚群和髓样抑制细胞亚群。随后，全面分析治疗前后免疫微环境的变化。

结果：晚期 NSCLC 患者的主要临床表现包括肺脾气虚证和气阴两虚证。值得注意的是，后者对 ICI 反应更为敏感，免疫微环境明显改善。接受 ICI 治疗后，三种菌株（梭菌、lachnospiraceae 和lachnospirales）的微生物丰度发生显著变化，存在相互依存关系。在表现出阳性 PD-L1 表达和持久治疗获益的患者亚组中，研究记录了 T 淋巴细胞亚群中 CD3%、CD4%和 CD4/CD8 的比例显著增加。相反，CD8%、Treg/CD4、M-MDSC/MDSC 和 G-MDSC/MDSC 的比例降低。

结论：Clostridia、lachnospiraceae 和lachnospirales 菌株可能成为 NSCLC 治疗中肠道微生物群组成的潜在生物标志物。在表现出持久治疗获益和阳性 PD-L1 表达的患者中，ICI 的免疫治疗疗效显著增强。