Postdoctoral Researcher Inst. Gustave Roussy Villejuif Cedex, France
Disclosure(s):
Andrew Almonte, PhD: No financial relationships to disclose
Introduction/Rationale: Evidence continues to link gut microbial dysbiosis with immunotherapy resistance. Patients with reduced responsiveness often lose beneficial bacteria such as Akkermansia muciniphila while gaining taxa detrimental to treatment outcomes. However, whether this dysbiosis is a cause or consequence of altered host immunity remains unresolved.
Methods: We investigated the immunological drivers of dysbiosis using a combination of flow cytometry, serology, T-cell profiling, and mouse models. Patient samples from NSCLC cohorts were analysed for anti-A. muciniphila IgG titres and recall T-cell responses. Parallel experiments in mice involved serum and splenocyte transfer following allogenic faecal microbiota transplantation (FMT), as well as antibody treatment experiments to evaluate the capacity of IgG to transcytose into the gut lumen and deplete gut commensals.
Results: High titres of anti-A. muciniphila IgG correlated with the depletion of the bacterium in NSCLC patients. Elevated titres, together with Th17/Th1 recall responses, were associated with poorer survival, increased frequencies of regulatory T-cells, and reduced effector populations. In murine models, serum transfer – but not splenocyte transfer – after allogenic FMT promoted tumour growth. Furthermore, studies using an in-house antibody derived from tumour-infiltrating B cells demonstrated that circulating IgG can cross the gut barrier to bind and eliminate its bacterial target.
Conclusion: These findings reveal that humoral immunity can directly shape gut microbial composition by promoting the loss of beneficial commensals such as A. muciniphila. This immune-driven dysbiosis may contribute to resistance against immune checkpoint blockade and underscores the need to consider host antibody responses when designing microbiota-centred interventions to enhance cancer immunotherapy outcomes.
