SCI

16 August 2024

Intratumoral Escherichia Is Associated With Improved Survival to Single-Agent Immune Checkpoint Inhibition in Patients With Advanced Non–Small-Cell Lung Cancer

（IF: JCO., 42.1）

  • Elkrief A, Montesion M, Sivakumar S, Hale C, Bowman AS, Begüm Bektaş A, Bradic M, Kang W, Chan E, Gogia P, Manova-Todorova K, Mata DA, Egger JV, Rizvi H, Socci ND, Kelly DW, Rosiek E, Meng F, Tam G, Fan N, Drilon A, Yu HA, Riely GJ, Rekhtman N, Quintanal Villalonga Á, Dogan S, Bhanot U, Gönen M, Loomis B, Hellmann MD, Schoenfeld AJ, Ladanyi M, Rudin CM, Vanderbilt CM. Intratumoral Escherichia Is Associated With Improved Survival to Single-Agent Immune Checkpoint Inhibition in Patients With Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2024 Jul 22:JCO2301488. 

  • CORRESPONDING AUTHOR ：Charles M. Rudin, MD, PhD; e-mail: rudinc@mskcc.org.

PURPOSE 目的

The impact of the intratumoral microbiome on immune checkpoint inhibitor (ICI) efficacy in patients with non–small-cell lung cancer (NSCLC) is unknown. Preclinically, intratumoral Escherichia is associated with a proinflammatory tumor microenvironment and decreased metastases. We sought to determine whether intratumoral Escherichia is associated with outcome to ICI in patients with NSCLC.

肿瘤内微生物组对非小细胞肺癌（NSCLC）患者免疫检查点抑制剂（ICI）疗效的影响尚不清楚。临床前研究中表明，肿瘤内大肠杆菌与促炎症肿瘤微环境与转移减少相关。我们试图确定肿瘤内大肠杆菌是否与NSCLC患者ICI的预后相关。

 

PATIENTS AND METHODS 患者与方法

We examined the intratumoral microbiome in 958 patients with advanced NSCLC treated with ICI by querying unmapped next-generation sequencing reads against a bacterial genome database. Putative environmental contaminants were filtered using no-template controls (n＝2,378). The impact of intratumoral Escherichia detection on overall survival (OS) was assessed using univariable and multivariable analyses. The findings were further validated in an external independent cohort of 772 patients. Escherichia fluorescence in situ hybridization (FISH) and transcriptomic profiling were performed.

我们检查了958名接受ICI治疗的晚期NSCLC患者的肿瘤内微生物组，通过查询细菌基因组数据库中未映射的二代测序读数与细菌基因组数据库进行比较。使用无模板对照（n = 2,378）过滤假定的环境污染物。使用单变量和多变量分析评估了瘤内检测大肠杆菌对总生存期（OS）的影响。这些发现在772名患者的外部独立队列中得到了进一步验证。进行了大肠杆菌荧光原位杂交（FISH）和转录组分析。

 

RESULTS 结果

In the discovery cohort, read mapping to intratumoral Escherichia was associated with significantly longer OS (16 v 11 months; hazard ratio, 0.73 [95% CI, 0.59 to 0.92]; P＝.0065) in patients treated with single-agent ICI, but not combination chemoimmunotherapy. The association with OS in the single-agent ICI cohort remained statistically significant in multivariable analysis adjusting for prognostic features including PD-L1 expression (P＝.023). Analysis of an external validation cohort confirmed the association with improved OS in univariable and multivariable analyses of patients treated with single-agent ICI, and not in patients treated with chemoimmunotherapy. Escherichia localization within tumor cells was supported by coregistration of FISH staining and serial hematoxylin and eosin sections. Transcriptomic analysis correlated Escherichia-positive samples with expression signatures of immune cell infiltration. 

在发现队列中，将读数映射到肿瘤内大肠杆菌与接受单药ICI治疗的患者的OS显著延长相关（16个月对比11个月；危险比，0.73 [95% CI, 0.59至0.92]; P＝.0065），但在接受联合化疗免疫治疗的患者中则无关。在校正了包括PD-L1表达在内的预后特征的多变量分析中，单药ICI队列中与OS的关联仍然具有统计学意义（P＝.023）。在外部验证队列的分析中，单药ICI治疗的患者在单变量和多变量分析中与改善的OS相关，而在接受化疗免疫治疗的患者中则不然。FISH染色和连续苏木精和伊红切片的配准支持了肿瘤细胞内大肠杆菌的定位。转录组学分析将大肠杆菌阳性样本与免疫细胞浸润的表达特征相关联。

 

CONCLUSION 结论

Read mapping to potential intratumoral Escherichia was associated with survival to single-agent ICI in two independent cohorts of patients with NSCLC.

在两组独立的NSCLC患者中，读取潜在肿瘤内大肠杆菌的映射与单药ICI的生存率相关。