肠道菌群组成影响肾细胞癌患者对肿瘤免疫治疗的应答
创作:aluba 审核:aluba 2020年05月18日
  • 纳入69名接受纳武单抗治疗的肾细胞癌患者;
  • 近期的抗生素使用显著改变了患者的肠道菌群组成,促进了Clostridium hathewayi的富集,后者在肾细胞癌患者中相比于健康人有所增加;
  • 11名近期使用过抗生素的患者的客观应答率显著降低(9% vs. 28%);
  • 在使用纳武单抗之前使用酪氨酸激酶抑制剂也可导致肠道菌群组成的变化,可能抑制ICI的疗效;
  • 粪菌移植实验在小鼠中证实了菌群组成与ICI疗效的因果关联。
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aluba
多项研究报道了肠道菌群组成影响癌症患者对免疫检查点抑制剂(ICI)治疗的应答,但尚无在肾细胞癌中的相关研究。European Urology上发表的一项最新研究,在接受纳武单抗治疗的69名肾细胞癌患者中发现,近期抗生素使用可改变肠道菌群组成,并降低患者的客观应答率。将应答患者的菌群或有益于ICI治疗的菌种(在应答患者中富集)移植给荷瘤小鼠可增强后者对ICI治疗的应答。另外,在使用纳武单抗之前使用酪氨酸激酶抑制剂,也可能引发不利于ICI治疗的菌群变化。
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European Urology [IF:24.267]

Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

肠道菌群组成驱动肾细胞癌患者对肿瘤免疫治疗的原发性耐药

10.1016/j.eururo.2020.04.044

2020-05-04, Article

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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 NIVOREN 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.

First Authors:
Lisa Derosa,Bertrand Routy,Marine Fidelle,Laurence Albiges,Laurence Zitvogel

Correspondence Authors:
Lisa Derosa,Laurence Zitvogel

All Authors:
Lisa Derosa,Bertrand Routy,Marine Fidelle,Valerio Iebba,Laurie Alla,Edoardo Pasolli,Nicola Segata,Aude Desnoyer,Filippo Pietrantonio,Gladys Ferrere,Jean-Eudes Fahrner,Emmanuelle Le Chatellier,Nicolas Pons,Nathalie Galleron,Hugo Roume,Connie Duong,Laura Mondragón,Kristina Iribarren,Mélodie Bonvalet,Safae Terrisse,Conrad Rauber,Anne-Gaëlle Goubet,Romain Daillère,Fabien Lemaitre,Anna Reni,Beatrice Casu,Maryam Tidjani Alou,Carolina Alves Costa Silva,Didier Raoult,Karim Fizazi,Bernard Escudier,Guido Kroemer,Laurence Albiges,Laurence Zitvogel

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