Abstract：
Strategies to modify the gut microbiome in cancer patients using fecal microbiota transplantation (FMT) have gained momentum as a therapeutic intervention. However, how FMT impacts innate-like, antimicrobial T lymphocytes is unclear. In this study, we assessed peripheral blood (PB) mucosa-associated invariant T (MAIT) cell frequencies and functions in patients with metastatic renal cell carcinoma (mRCC) before and seven days after they received FMT as part of a clinical trial. We found comparable MAIT cell frequencies in healthy controls and mRCC patients. In contrast, γδ T cells exhibited a numerical decline in mRCC, which was partially reversed by FMT. We also found a significant increase in the PB CD4+ MAIT cell compartment of mRCC patients with or without FMT. Paired sample analyses revealed CD69 upregulation on MAIT cells accompanied by decreased PD-1 levels post-FMT. These changes were unique to MAIT cells as non-MAIT T lymphocytes showed either no trend or a trend in the opposite direction. Importantly, FMT did not render MAIT cells exhausted as also judged by their stable expression of TIM-3, LAG-3, BTLA, CTLA-4, TIGIT and VISTA. These findings were corroborated in functional assays in which MAIT cells were stimulated with MR1 ligands or with a combination of IL-12 and IL-18 to produce inflammatory cytokines and granzyme B. Indeed, when stimulated ex vivo with IL-12 and IL-18, MAIT cells mounted a more rigorous TNF-α response post-FMT. In conclusion, FMT improves MAIT cell functions, which should serve patients well in subsequent microbial challenges in the face of cancer-elicited immunosuppression. Trial Registration: https://clinicaltrials.gov/ Identifier: NCT04163289 (registration date: November 14, 2019).
摘要：
使用粪便微生物群移植（FMT）修饰癌症患者肠道微生物组的策略作为治疗干预措施已经获得了动力。然而,FMT如何影响先天，抗菌T淋巴细胞尚不清楚。在这项研究中,作为临床试验的一部分,我们评估了转移性肾细胞癌(mRCC)患者在接受FMT治疗前和治疗后7天的外周血(PB)粘膜相关不变T(MAIT)细胞频率和功能.我们在健康对照和mRCC患者中发现了相当的MAIT细胞频率。相比之下,γδT细胞表现出mRCC的数值下降，FMT部分逆转了。我们还发现有或没有FMT的mRCC患者的PBCD4MAIT细胞区室显着增加。配对样品分析显示MAIT细胞上的CD69上调伴随FMT后PD-1水平降低。这些变化对于MAIT细胞是独特的，因为非MAITT淋巴细胞没有趋势或呈相反方向的趋势。重要的是,FMT不会使MAIT细胞耗尽，如通过TIM-3，LAG-3，BTLA，CTLA-4、TIGIT和VISTA。这些发现在功能测定中得到证实，在功能测定中，用MR1配体或用IL-12和IL-18的组合刺激MAIT细胞以产生炎性细胞因子和颗粒酶B。当用IL-12和IL-18离体刺激时,MAIT细胞在FMT后产生更严格的TNF-α应答。总之,FMT改善MAIT单元功能，在随后的微生物挑战中，面对癌症引发的免疫抑制，这应该为患者提供良好的服务。试用注册：https://clinicaltrials.gov/Identifier：NCT04163289（注册日期：2019年11月14日）。
