Guardamagna Mora, Berciano-Guerrero Miguel-Angel, Lavado-Valenzuela Rocío, Auclin Édouard, Onieva-Zafra Juan Luis, Plaza-Andrades Isaac, Oliver Javier, Garrido-Aranda Alicia, Perez-Ruiz Elisabeth, Álvarez Martina, Ocaña María Carmen, Queipo-Ortuño María Isabel, Barragán Isabel, Rueda-Dominguez Antonio
Virgen de la Victoria University Hospital, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29010, Málaga, Spain.
Department of Medicine and Dermatology, Medical School University of Málaga, Campus Teatinos, Blvr. Louis Pasteur, 32, 29010, Málaga, Spain.
Sci Rep. 2025 Jul 14;15(1):25430. doi: 10.1038/s41598-025-11054-2.
Gut microbiota has been associated with carcinogenesis and immune regulation. While there is evidence supporting its influence on immunotherapy response in melanoma, its impact on BRAF/MEK-targeted therapy remains unexplored. This study assessed gut microbiota composition and immune-associated genes in melanoma, to generate hypothesis on prognostic and predictive biomarkers for BRAF/MEK inhibitor therapy. This prospective, observational study analyzed fecal and blood samples from 26 patients diagnosed with BRAF-mutated metastatic melanoma. Samples were collected at baseline (T0) and at first radiological evaluation (T1). Patients were stratified by treatment response and toxicity. Partial responders had baseline enrichment of Lachnospiraceae, Coriobacteriaceae, and Adlercreutzia. Complete responders showed abundance of Prevotellaceae, Cerasicoccaceae and Lawsonia. Oscillospira was associated with moderate-to-severe toxicity. Gene expression analysis revealed upregulation of TAP1 y PSMB8 during treatment in responders, with persistent downregulation of LAG3, CD36, SLAMF7, NOD1, SLAMF6, CX3CR1 and ICAM2. Overall, baseline microbiota composition differed by response depth, with abundance of Lachnospiraceae, Coriobacteriaceae, and Adlercreutzia in partial responders and Prevotellaceae, Cerasicoccaceae, and Lawsonia in complete responders. A gene signature of immune-suppresive genes was persistently downregulated in responders. Our findings suggest that specific gut microbial taxa and immune-related gene expression patterns may be associated with differential responses to BRAF/MEK-targeted therapy in metastatic melanoma.
肠道微生物群与癌症发生和免疫调节有关。虽然有证据支持其对黑色素瘤免疫治疗反应的影响，但其对BRAF/MEK靶向治疗的影响仍未得到探索。本研究评估了黑色素瘤患者的肠道微生物群组成和免疫相关基因，以生成关于BRAF/MEK抑制剂治疗的预后和预测生物标志物的假设。这项前瞻性观察性研究分析了26例诊断为BRAF突变转移性黑色素瘤患者的粪便和血液样本。样本在基线（T0）和首次影像学评估（T1）时采集。患者按治疗反应和毒性进行分层。部分缓解者在基线时Lachnospiraceae、Coriobacteriaceae和Adlercreutzia富集。完全缓解者显示Prevotellaceae、Cerasicoccaceae和Lawsonia丰富。Oscillospira与中度至重度毒性相关。基因表达分析显示，治疗期间缓解者中TAP1和PSMB8上调，而LAG3、CD36、SLAMF7、NOD1、SLAMF6、CX3CR1和ICAM2持续下调。总体而言，基线微生物群组成因反应深度而异，部分缓解者中Lachnospiraceae、Coriobacteriaceae和Adlercreutzia丰富，完全缓解者中Prevotellaceae、Cerasicoccaceae和Lawsonia丰富。免疫抑制基因的基因特征在缓解者中持续下调。我们的研究结果表明，特定的肠道微生物分类群和免疫相关基因表达模式可能与转移性黑色素瘤对BRAF/MEK靶向治疗的不同反应有关。
