Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients
Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients
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DOI：
10.1016/j.eururo.2020.04.044
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发表时间：
2020-08-01
期刊：
影响因子：
23.4
通讯作者：
Zitvogel, Laurence
中科院分区：
文献类型：
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作者：
Derosa, Lisa;Routy, Bertrand;Zitvogel, Laurence
背景：免疫检查点阻断(ICB)的发展使肾癌(RCC)的临床结局发生了革命性的变化。然而，耐久性的改善和反应的预测仍然没有满足医疗需求。虽然人们已经认识到抗生素(ATB)会降低ICB在各种恶性肿瘤中的临床活性，但对于不同的肠道非致病菌(共生菌)对ICB治疗结果的直接影响知之甚少。目的：评估粪便细菌组成对ICB疗效的预测价值在一组晚期RCC患者中。设计、环境和参与者：我们前瞻性地收集了69名接受nivolumab治疗的晚期RCC患者的粪便样本，并在Gustave Roussy参加了GETUG-AFU 26 Nivo-Ren微生物亚研究第二阶段试验(NCT03013335)。我们记录了患者的特征，包括ATB的使用，先前的系统治疗，以及反应标准。我们分析了2994份来自健康志愿者(HV)的粪便样本。同时，对接受ICB耐药肾癌患者粪便移植(FMT)的RCC荷瘤小鼠进行的临床前研究使我们能够得出肠道细菌组成与ICB临床结果之间的因果关系。结果和统计分析：来自全基因组测序(WGS)的元基因组数据(MG)通过多变量和成对比较/倍率分析，以确定与ATB或先前TKI暴露和患者的治疗反应(总体反应和无进展生存)相关的细菌指纹，并与无癌捐赠者的数据进行比较。结果与限制：最近使用ATB(n=11；16%)降低了客观应答率(从28%降至9%，p<；0.03)，并显著影响微生物区系的组成，促进了不同物种的优势，如哈氏梭菌，与人类相比，哈氏梭菌在肾癌患者的粪便中也有更高的表达。重要的是，在nivolumab之前服用的TKI在改变微生物区系组成方面有影响。为了建立肠道细菌组成与ICB疗效之间的因果关系，用应答的肾癌患者的FMT或WGS-MG确定的有益共生体(Akkermansia稠iniPhila和Bacteroids salyersiae)成功地补偿了NR-FMT小鼠。结论：TKI和ATBS影响微生物区系的组成，并影响免疫治疗的成功。未来的研究将有助于加强这些特定细菌的作用及其作为新生物标志物的潜力。患者摘要：我们使用粪便微生物的定量DNA测序以及临床前粪便或细菌转移模型来研究粪便成分与免疫检查点阻断(Pre)临床结果之间的关系。对肠道微生物失调在肾癌预后中的病理生理学相关性的新见解可能会导致创新的治疗方案，如补充益生菌以防止原发耐药。(C)2020年，爱思唯尔公司代表欧洲泌尿学协会出版。
Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC.Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVO-REN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/ fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors.Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae).Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers.Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. (c) 2020 Published by Elsevier B.V. on behalf of European Association of Urology.