Natural Killer (NK) cell-mediated Antibody Dependent Cellular Cytotoxicity (ADCC), based on the recognition of IgG-opsonized targets by the low affinity receptor for IgG Fc¿RIIIA/CD16, represents one of the main mechanisms by which therapeutic antibodies (mAbs) mediate their anti-tumor effects. Beside ADCC, CD16 ligation also results in cytokine production, in particular, NK-derived IFN-¿ is endowed with a well recognized role in the shaping of adaptive immune responses.
Obinutuzumab is a glycoengineered anti-CD20 mAb with a modified 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 optimised affinity conditions on NK functional program is not completely understood.
We recently demonstrated a relationship between CD16 aggregation conditions and the ability to induce a shift of NK functional program. Indeed, the interaction of NK cells with obinutuzumab-opsonized cells results in the increased ability to produce IFN-¿ in response to different stimula, as compared with parental non-glycoengineered mAb or the reference molecule rituximab.
In the present project we will address whether the interaction of NK cells with obinutuzumab-opsonised targets may dictate an epigenetic imprinting responsible for the priming for IFN-¿ production thus revealing a relationship between CD16 affinity ligation conditions and the epigenetic reprogramming of human NK cells in a therapeutic setting. In particular we will study the epigenetic signature in obinutuzumab-experienced NK cells, with particular attention to regulation of the IFNG locus.
We strongly believe that the results of this research project will provide informations with a strong translational potential.
We strongly believe that the results of this research project will provide informations with a strong translational potential. In particular will allow to:
1. appreciate the distinct capability of a glyco-engineered mAb to drive a shift in NK functional program which may impact on the clinical response and immuno-competence of anti-CD20-treated patients;
2. provide a mechanistic explanation of the ability of NK cells to support the generation of a long-lasting anti-tumor adaptive immune response (vaccinal effect) in response to mAbbased therapeutic strategies.
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