The FcγRs-Dependent IgG-Mediated ADCC/ADCP Effector Functions Are Influenced by a Microbiome Modulation

Introduction: Monoclonal antibody (mAb)-based immunotherapies revolutionized cancer treatment over the last two decades. Based on their mode of action, we can classify these therapies into two groups: mAbs directly targeting the tumor, and those targeting immune checkpoint. The cellular receptor of antibodies, Fc-gamma receptors (FcγRs), play important role in mediating the therapeutic activity of mAbs from these two types. Recent studies demonstrated that the gut microbiota tightly regulates immunotherapies efficacy and toxicity. Here, we set out to decipher the role of the microbiome in the FcγRs-mediated anti-tumor function. We aim to correlate a microbiome disruption with a modulation of the FcγR-mediated IgG functions, in different immunological organs and immune context.

Material and Method: The gut microbiota was depleted via a broad cocktail of antibiotics diluted in the drinking water during either 2 or 4 week long. We analyzed by flow cytometry the FcγRs expression profile in spleen and blood, as well as in the B16F10 tumor microenvironment (TME).

Results and Discussion: In the spleen, microbiome depletion induces a significant downregulation of all activating-FcγRs and the FcγRIII density, at the Red-Pulp macrophages and neutrophils cell surface, respectively. These cells are known to mediate Antibody-dependent cell cytotoxicity/phagocytosis (ADCC/ADCP) effector functions in the spleen. Therefore, our molecular data suggest an impairment of these functions. We are currently addressing it by relevant in vivo experiments. In the blood, only the FcγRI density on monocytes is negatively impaired by the microbiome disruption, conversely to the FcγRIII that is upregulated at 2 week of treatment. Although the monocyte population is well described as effector of the IgG-mediated ADCC/ADCP, in contrast to the FcγRIII, the FcγRI seems barely involved in those functions. Finally, in the skin-B16F10 TME, we observed an increased density of all activating-FcγRs on the tumor-associated macrophages consequently to the microbiome depletion. We hypothesize that this may potentiate the FcγRs-dependent IgG activity within the TME.

Conclusion: Here, by linking the FcγRs expression pattern and the microbiome integrity, we gathered preliminary data suggesting a subsequent mAb-mediated effector function modulation. Our data imply on novel mAb’s anti-tumor and toxic mechanisms, and may pave a way to optimize anti-cancer mAb-based immunotherapies.