Neoadjuvant pembrolizumab has been shown to be a valid treatment for patients affected by muscle-invasive bladder cancer (MIBC), as demonstrated in the PURE-01 clinical trial (NCT02736266). Among the tumor-extrinsic factors influencing immunotherapy efficacy, extensive data highlighted that the microbiome is a central player in immune-mediated anticancer activity. This report aimed to investigate the composition and role of stool microbiome in patients enrolled in the PURE-01 clinical trial. An orthotopic animal model of bladder cancer (MB49-Luc) was used to support some of the findings from human data. An analysis of stool microbiome before pembrolizumab was conducted for 42 patients, of whom 23 showed a pathologic response. The information in the preclinical model of orthotopic bladder cancer treated with anti–PD-1 antibody or control isotype was validated. Linear discriminant analysis effect size and linear models were used to identify the bacterial taxa enriched in either responders or nonresponders. The identified taxa were also tested for their association with event-free survival (EFS). Survival at 31 d after tumor instillation was used as the study endpoint in the preclinical model. Responders and nonresponders emerged to differ in terms of enrichment for 16 bacterial taxa. Of these, the genus was enriched in responders, while the species was enriched in nonresponders. The negative impact of on anti–PD-1 antibody activity was also observed in the preclinical model. EFS and survival of the preclinical model showed a negative role of . We found different stool bacterial taxa associated with the response or lack of response to neoadjuvant pembrolizumab. Moreover, we provided experimental data about the negative role of on immunotherapy response. Further studies are needed to externally validate our findings and provide mechanistic insights about the host-pathogen interactions in MIBC. Using prepembrolizumab stool samples collected from patients enrolled in the PURE-01 clinical trials, we identified some bacterial taxa that were enriched in patients who either responded or did not respond to immunotherapy. Using an animal model of bladder cancer, we gathered further evidence of the negative impact of the on immunotherapy efficacy. Further studies are needed to confirm the current findings and test the utility of these bacteria as predictive markers of immunotherapy response.

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粪便微生物组特征与肌层浸润性膀胱癌患者对新辅助派姆单抗的反应相关

正如 PURE-01 临床试验 (NCT02736266) 所证明的那样，新辅助派姆单抗已被证明是治疗肌层浸润性膀胱癌 (MIBC) 患者的有效方法。在影响免疫治疗疗效的肿瘤外在因素中，大量数据强调微生物组是免疫介导的抗癌活性的核心参与者。本报告旨在调查参加 PURE-01 临床试验的患者粪便微生物组的组成和作用。膀胱癌原位动物模型（MB49-Luc）被用来支持人类数据的一些发现。对 42 名患者使用派姆单抗前的粪便微生物组进行了分析，其中 23 名患者出现病理反应。使用抗 PD-1 抗体或对照同种型治疗的原位膀胱癌临床前模型中的信息得到了验证。使用线性判别分析效应大小和线性模型来识别响应者或非响应者中富集的细菌类群。还测试了所识别的分类单元与无事件生存（EFS）的关联。肿瘤灌注后 31 天的存活率被用作临床前模型的研究终点。有反应者和无反应者在 16 种细菌分类群的富集方面存在差异。其中，属中富含应答者，而物种中富含非应答者。在临床前模型中也观察到了对抗 PD-1 抗体活性的负面影响。 EFS对临床前模型的存活率呈负作用。我们发现不同的粪便细菌分类群与新辅助派姆单抗的反应或缺乏反应相关。此外，我们提供了关于免疫治疗反应的负面作用的实验数据。需要进一步的研究来从外部验证我们的研究结果，并提供有关 MIBC 中宿主与病原体相互作用的机制见解。使用从参加 PURE-01 临床试验的患者收集的 prepembrolizumab 粪便样本，我们确定了一些细菌类群，这些细菌类群在对免疫治疗有反应或无反应的患者中富集。使用膀胱癌的动物模型，我们收集了对免疫治疗功效产生负面影响的进一步证据。需要进一步的研究来证实目前的发现并测试这些细菌作为免疫治疗反应的预测标记物的效用。