Background
The gut microbiome’s role as a determinant of response to immune checkpoint inhibitors (ICI) has ignited interest in fecal microbiota transplantation (FMT) to augment clinical outcomes in advanced melanoma. Initial clinical trials suggest that FMT plus ICI could enhance the efficacy of treatment, including among previously ICI resistant patients. This study sought to identify specific post-FMT microbiome features linked to anti-PD-1 response, highlighting malleable elements that might possess therapeutic potential.
Methods
Longitudinal stool shotgun sequencing data aggregated from three Phase I clinical trials involving FMT and anti-PD-1 treatment in advanced melanoma patients were analyzed.1–3 Shotgun sequencing data underwent a rigorous pre-processing phase and cleaned reads were assembled into a custom database of Metagenome-Assembled Genomes (MAGs), which were assigned a taxonomic classification. The microbial relative abundance and gene count were computed for each donor and recipient sample, and distinct bacterial strains identified, defined by sharing over 99.99% average nucleotide identity. These features were compared between responders and non-responders to anti-PD-1.
Results
FMT was found to increase a recipient’s overall alpha diversity, but this change was not a predictor of subsequent anti-PD-1 response. Notably, enhanced patient responses correlated with a shift in the recipients’ microbiomes towards the donor’s profile post-FMT. The analysis also revealed a relation between higher frequency of donor strain acquisition and better responses, with different microbial pathways enriched among responders and non-responders. Notably, bacterial secretion system genes, usually linked with microbial pathogens, were more commonly transferred to individuals who would fail to respond to the therapy. The transfer of individual strains, species, or single genes, however, were not significantly associated with response, emphasizing the importance of comprehensive community-level changes through FMT in driving effective ICI response. Additionally, we found a correlation between FMT-induced microbiome alterations and immune cell changes within the tumor microenvironment.
Conclusions
These findings highlight the potential of FMT as a strategy to optimize ICI response in advanced melanoma patients. While no single element of the microbiome was significantly correlated with response, we anticipate community-level alterations in composition and function are likely necessary to improve outcomes. An understanding of gut microbiome function, for example, with transcriptomics and metabolomics, and how this intersects with the anti-tumor immune response are important next steps for the field. Further research should be aimed at understanding these interactions, paving the path to use microbiome modulation in combination with cancer immunotherapy.
References
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