Microbial Ecosystem Therapeutics 4 (MET4) elicits treatment-specific IgG responses associated with changes in gut microbiota in immune checkpoint inhibitor recipients with advanced solid tumors.

Background: Gut microbiome modulation has shown promise in its potential to treat cancer in combination with immunotherapy. Mechanistically, the pathways and routes by which gut microbiota may influence systemic and antitumor immunity remain uncertain. Here, we used blood and stool samples from Microbial Ecosystem Therapeutic 4 (MET4)-IO, an early-phase trial testing the safety and engraftment of the MET4 bacterial consortium in immune checkpoint inhibitor recipients, to assess how MET4 may affect systemic immunity.

Methods: Circulating antibody responses induced by MET4 were assessed using an antimicrobial antibody flow cytometry assay on pretreatment and post-treatment plasma. Antibody responses were associated with taxonomic changes in stool identified by metagenomic sequencing. Mass cytometry was performed on peripheral blood mononuclear cells to identify shifts in circulating immune subsets associated with antibody responses.

Results: Increases in circulating anti-MET4 immunoglobulin G (IgG) responses were measured by flow cytometry post-consortium treatment in MET4 recipients, but not untreated control participants, with five individuals displaying notably higher antibody responses. Stronger IgG responses were associated with greater increases in multiple taxa, including MET4 microbe Collinsella aerofaciens, which was previously linked with immune checkpoint response. However, these taxa were not enriched in the IgG-bound fraction post-MET4 treatment. Greater increases in circulating B cells and FoxP3⁺ CD4⁺ T cells post-MET4 treatment were observed in the blood of high IgG responders, while CD14⁺ and CD16⁺ monocyte populations were decreased in these individuals.

Conclusion: These results demonstrate the induction of treatment-specific circulating humoral immunity by a bacterial consortium and suggest potential mechanisms by which gut microbes may contribute to antitumor immunity.