肺癌免疫治疗中患者微生物组与免疫介导不良反应的发生和发展的前瞻性相关性。

BACKGROUND: Though the gut microbiome has been associated with efficacy of immunotherapy (ICI) in certain cancers, similar findings have not been identified for microbiomes from other body sites and their correlation to treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs. METHODS: We designed a prospective cohort study conducted from 2018 to 2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Patients must have had measurable disease, ECOG 0-2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Patients with histopathologically confirmed, advanced/metastatic LC planned to undergo immunotherapy-based treatment were enrolled between September 2018 and June 2019. Nasal, buccal and gut microbiome samples were obtained prior to initiation of immunotherapy +/- chemotherapy, at development of adverse events (irAEs), and at improvement of irAEs to grade 1 or less. RESULTS: Thirty-seven patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium (p = 0.001) and Desulfovibrio (p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales (p = 0.018) but reduced Rikenellaceae (p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. CONCLUSIONS: This pilot study identifies significant differences in the gut microbiome between HC and LC patients, and their correlation to treatment response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03688347 . Retrospectively registered 09/28/2018.

背景：尽管肠道微生物群与某些癌症的免疫疗法（ICI）疗效有关，但尚未在其他身体部位的微生物群中发现类似的发现，也未发现它们与接受 ICI 治疗的肺癌（LC）患者的治疗反应和免疫相关不良事件（irAE）之间存在相关性。

方法：我们设计了一项前瞻性队列研究，于 2018 年至 2020 年在一家单中心学术机构进行，以评估来自不同身体部位的微生物组与 LC 患者接受 ICI 治疗时的治疗反应和 irAE 发展之间的相关性。必须有可测量的疾病、ECOG 0-2 和良好的器官功能才能入组。数据于 2019 年 1 月至 2020 年 10 月收集进行分析。2018 年 9 月至 2019 年 6 月，入组接受组织病理学证实的晚期/转移性 LC 计划接受免疫治疗的患者。在开始免疫治疗 +/- 化疗之前、发生不良事件（irAE）时以及 irAE 改善至 1 级或更低时，获得鼻、颊和肠道微生物组样本。

结果：共纳入 37 例患者，其中 34 例患者可用于本报告。为了比较基线肠道微生物群，纳入了来自同一地理区域的 32 名健康对照（HC）。与 HC 相比，LC 肠道微生物群的 α 多样性明显降低。未发生 irAE 的患者肠道微生物群中双歧杆菌（p=0.001）和脱硫弧菌（p=0.0002）相对富集。联合化疗免疫治疗的应答者表现出梭状芽胞杆菌（p=0.018）增加，但雷克林氏菌科（p=0.016）减少。在化疗免疫治疗的应答者中，我们还观察到鼻腔微生物群中金星菌的富集，以及颊样本中巨球形菌的增加和放线杆菌的减少。纵向样本在 irAE 的发展和解决过程中表现出 α 多样性和某些微生物变化的趋势。

结论：这项初步研究确定了 HC 和 LC 患者之间肠道微生物群的显著差异，以及它们与 LC 患者的治疗反应和 irAE 的相关性。此外，它还表明鼻腔和颊部微生物群具有潜在的预测效用，值得进一步用更大的队列进行验证，并使用临床前模型进行机制分析。

试验注册：ClinicalTrials.gov，NCT03688347。2018 年 9 月 28 日回顾性注册。