Association of gut microbiota and immune gene expression with response to targeted therapy in BRAF mutated melanoma

Abstract

Abstract 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.