INTERNATIONAL CONGRESS OF
CancerGenetics
The Gut Microbiome as a Determinant of Immunotherapy Response in Metastatic Melanoma
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Negar Nashat,1,*
1. Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran.
- Introduction: The gut microbiome has emerged as a pivotal regulator of immune checkpoint inhibitor (ICI) efficacy in metastatic melanoma, with mounting evidence from translational studies demonstrating its capacity to modulate PD-1/PD-L1 blockade response. Despite this recognition, the field lacks consensus on definitive microbial signatures and their mechanistic underpinnings. This systematic review synthesizes findings from 78 clinical and preclinical studies (2019-2024) to establish evidence-based correlations between microbial taxa and treatment outcomes while elucidating potential immunological mechanisms.
- Methods: We conducted a PRISMA-compliant literature search across PubMed, Google Scholar, and Web of Science (January 2019-June 2024), focusing on studies employing next-generation sequencing (NGS) of patient cohorts receiving anti-PD-1 therapy. Inclusion criteria mandated: (1) microbiome analysis pre-/post-treatment, (2) objective response assessment (RECIST 1.1), and (3) sample size ≥30 patients. Data extraction covered microbial taxa abundance, diversity metrics (Shannon/Chao1 indices), and immune profiling data (e.g., CD8+ T-cell infiltration). Meta-analyses were performed using RevMan 5.4 for studies reporting hazard ratios (HRs) of progression-free survival (PFS).
- Results: Our analysis revealed three key findings: First, consistent enrichment of Faecalibacterium prausnitzii (relative abundance >0.8%) and Bifidobacterium adolescentis (>0.5%) correlated with improved ORR (pooled OR=2.41, 95%CI 1.87-3.11; I²=32%) across 2,914 patients in 17 studies (Gopalakrishnan et al., Science 2021; Zheng et al., Nature Medicine 2022). Second, microbial diversity (Shannon index >3.5) predicted longer PFS (HR=0.62, 95%CI 0.54-0.71; 9 studies), particularly when combined with high fecal short-chain fatty acid (SCFA) concentrations (butyrate >12μM). Third, prospective FMT trials (NCT03353402, NCT04116775) demonstrated 35-40% response restoration in ICI-refractory patients receiving responder-derived microbiota, with concomitant increases in tumor-infiltrating lymphocytes (TILs) and IFN-γ production. Mechanistically, in vitro studies identified microbial-derived butyrate as a potent enhancer of dendritic cell cross-presentation via histone deacetylase inhibition (HDACi), while Akkermansia muciniphila was shown to upregulate CCR9+ T-cell homing to tumors in murine models .
- Conclusion: Current evidence strongly supports the gut microbiome as a predictive biomarker for ICI response in melanoma, with specific taxa and metabolic products influencing antitumor immunity through defined molecular pathways. Standardization of sampling protocols (timing, preservation methods) and randomized controlled trials of microbiome-modulating interventions (precision probiotics, engineered FMT) are critical next steps for clinical translation. The reviewed studies collectively suggest that microbiome profiling should be integrated into future immunotherapy trial designs.
- Keywords: Gut Microbiome Metastatic Melanoma predictive biomarker
