Humoral immunity against gut commensals governs their prevalence and influences patient clinical outcome 2267972

Abstract

Abstract Introduction 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. Funding Source This work was supported by the French Ministry of Health (PIA5, ANR, RHU5 ‘‘ANR-21-RHUS-0017’’ IMMUNOLIFE); the European Union’s Horizon 2020 programme (grant agreements 964590, IHMCSA; 825410, ONCOBIOME — Gut OncoMicrobiome Signatures associated with cancer incidence, prognosis, and treatment response prediction); the Horizon Europe programme (grant 101095604, PREVALUNG EU — Biomarkers affecting the transition from cardiovascular disease to lung cancer for stratified interception); the ANR grant Ileobiome (ANR-19-CE15-0029-01); the European Research Council (ERC) under grant 101052444 (ICD-Cancer — Immunogenic cell death in the cancer-immune dialogue); and by the SIRIC SOCRATE and SIGN’IT ARC Foundation programmes (MICROBIONT-PREDICT, 2021; Made-IT, 2023). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)