Natural Killer (NK) cell-mediated Antibody Dependent Cellular Cytotoxicity (ADCC), based on the recognition of IgG-opsonized targets by the low affinity Fc receptor for IgG FcgammaRIIIA/CD16, represents one of the main mechanisms by which therapeutic monoclonal antibodies (mAbs) mediate their anti-tumor effects. Besides ADCC, CD16 ligation also results in production of cytokines such as IFN-gamma that plays a key role in the shaping of adaptive immune responses.
Obinutuzumab is a humanized type II anti-CD20 mAb of 3rd generation with a glycoengineered crystallizable fragment (Fc) domain designed to increase the affinity for CD16 and consequently the killing of mAb-opsonized targets. However, the impact of CD16 ligation in optimized affinity conditions on NK functional program is not completely understood.
We recently demonstrated that the interaction of NK cells with obinutuzumab-opsonized tumor B cells leads to an enhanced IFN-gamma production in response to a subsequent stimulation, as compared with the parental non-glycoengineered mAb or the reference molecule rituximab.
In the present project I will analyse the impact of CD16 aggregation conditions on the modulation of the levels of selected miRNAs and their role in the shift of NK functional program in a therapeutic setting.
I believe that the results of this research project will provide information with a strong translational potential. In particular, it will allow to unveil the molecular mechanisms underlying the functional priming of NK cells in a therapeutic setting which may impact on the clinical response and immuno-competence of anti-CD20-treated patients.