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INTERNATIONAL CONGRESS OF

CancerGenetics

• The Gut Microbiome's Role in Modulating PD-1/PD-L1 Immunotherapy Efficacy in Melanoma

• Arman Taran,^1,* Mina Shirmohammadpour,² Bahman Mirzaei,³
  1. Department of Microbiology and Virology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
  2. Department of Microbiology and Virology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
  3. Department of Biostatistics and Epidemiology, Faculty of Medicine, Zanjan University of Medical Sciences
  
  
  
• Introduction: The relationship between gut microbial communities and immune checkpoint inhibitor response represents one of the most significant breakthroughs in personalized cancer therapy. In melanoma treatment, where PD-1/PD-L1 inhibitors have become cornerstone therapies, approximately half of patients still fail to respond. A growing body of evidence suggests that intestinal bacteria play a crucial role in shaping systemic immune responses through multiple mechanisms. Certain bacterial species appear to enhance antitumor immunity by stimulating dendritic cell maturation, promoting T-cell infiltration into tumors, and maintaining intestinal barrier integrity. Conversely, microbiome dysbiosis may contribute to immunotherapy resistance through the expansion of immunosuppressive cell populations. This review examines the complex interplay between gut microbiota composition and PD-1/PD-L1 inhibitor efficacy, focusing specifically on melanoma treatment outcomes.
• Methods: Our comprehensive analysis incorporated data from 42 peer-reviewed studies published between 2016 and 2023, including both clinical observations and mechanistic investigations. We systematically evaluated clinical trials that correlated baseline microbiome features with treatment response in over 1,500 melanoma patients receiving anti-PD-1/PD-L1 therapy. Laboratory studies exploring microbial influences on immune cell function were analyzed, particularly those investigating bacterial metabolites and their effects on T-cell activation. Intervention studies involving microbiome modification approaches were critically assessed, including fecal microbiota transplantation trials and dietary intervention studies. Statistical analyses focused on consistent patterns across different cohorts and experimental systems.
• Results: The analysis revealed several key findings regarding microbiome-immune interactions in melanoma treatment. Patients exhibiting higher baseline abundance of Akkermansia muciniphila demonstrated significantly improved response rates to PD-1 blockade, with objective response rates nearly doubling compared to patients lacking this bacterium. Mechanistic studies showed that this microbe enhances cross-presentation of tumor antigens by dendritic cells and promotes the expansion of memory T-cell populations. Butyrate-producing bacteria, particularly Faecalibacterium prausnitzii, were associated with increased intratumoral CD8+ T-cell infiltration and improved progression-free survival. Conversely, enrichment of Bacteroides species correlated with poorer outcomes, potentially through induction of regulatory T cells. Intervention studies demonstrated that modifying the gut microbiome could improve treatment outcomes. Fecal microbiota transplantation from responding patients to non-responders resulted in clinical responses in approximately 30% of cases, accompanied by favorable changes in immune cell profiles. Dietary interventions emphasizing high-fiber intake were associated with beneficial microbiome shifts and enhanced immunotherapy efficacy. Probiotic supplementation trials showed mixed results, highlighting the complexity of microbial ecosystem engineering.
• Conclusion: The gut microbiome represents a potentially modifiable factor influencing PD-1/PD-L1 inhibitor efficacy in melanoma. While significant progress has been made in identifying response-associated microbial signatures, several challenges remain. Standardization of microbiome analysis methods across institutions is needed, along with larger prospective studies to validate predictive biomarkers. The development of targeted microbiome-modulating interventions, whether through precision probiotics, phage therapy, or dietary approaches, holds promise for improving outcomes in melanoma immunotherapy. Future research should focus on elucidating the precise molecular mechanisms linking specific bacterial strains to immune activation, which could lead to novel therapeutic strategies for overcoming immunotherapy resistance.
• Keywords: gut microbiome, melanoma, PD-1 inhibitors, immunotherapy, microbial biomarkers