Angeli D.G. Macandog, Carlotta Catozzi, Mariaelena Capone, Amir Nabinejad, Padma P. Nanaware, Shujing Liu, Smita Vinjamuri, Johanna A. Stunnenberg, Serena Galiè, Maria Giovanna Jodice, Francesca Montani, Federica Armanini, Ester Cassano, Gabriele Madonna, Domenico Mallardo, Benedetta Mazzi, Salvatore Pece, Maria Tagliamonte, Vito Vanella, Massimo Barberis, Luigi Nezi
{"title":"抗 PD-1 治疗期间肠道微生物群的纵向分析揭示了黑色素瘤患者反应的稳定微生物特征","authors":"Angeli D.G. Macandog, Carlotta Catozzi, Mariaelena Capone, Amir Nabinejad, Padma P. Nanaware, Shujing Liu, Smita Vinjamuri, Johanna A. Stunnenberg, Serena Galiè, Maria Giovanna Jodice, Francesca Montani, Federica Armanini, Ester Cassano, Gabriele Madonna, Domenico Mallardo, Benedetta Mazzi, Salvatore Pece, Maria Tagliamonte, Vito Vanella, Massimo Barberis, Luigi Nezi","doi":"10.1016/j.chom.2024.10.006","DOIUrl":null,"url":null,"abstract":"Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. 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引用次数: 0
摘要
免疫检查点抑制剂(ICIs)可改善晚期黑色素瘤的治疗效果,但许多患者会出现难治性或复发。肠道微生物群调节抗肿瘤反应。然而,不一致的基线预测因素导致了反应的异质性和横断面数据的不足。我们对无法切除的黑色素瘤患者进行了基线和抗PD-1治疗期间的随访,收集粪便和血液样本,调查肠道微生物群和免疫标记物的变化。在 ICI 治疗期间,患者不同的反应与不同的肠道微生物群动态有关。我们通过稳定的微生物群功能筛选出完全应答者,并通过多个外部队列和实验进行验证。我们确定了主要组织相容性复合体 I 类(MHC I 类)限制肽,这些肽来源于拉赫诺斯皮拉科(Lachnospiraceae)鞭毛蛋白相关基因(FLach),是肿瘤相关抗原的结构同源物,在 ICI 治疗前检测到完全应答者中的 FLach 反应性 CD8+ T 细胞,并证明 FLach 肽能提高抗肿瘤免疫力。这些发现凸显了微生物功能的预后价值和仿肿瘤微生物肽的治疗潜力。
Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients
Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.