Impact of tumor-targeting mAbs on the molecular and functional features of Memory Natural Killer cells: an in vitro and in vivo study
Natural Killer (NK) cell-mediated effector functions significantly contribute to anti-tumor activity of tumor targeting monoclonal antibodies (mAbs): indeed, CD16 (FcgammaRIIIa) aggregation by means of opsonised targets not only triggers tumor cell killing but may also favour the development of long lasting IFN-gamma-dependent anti-tumor T cell responses. Notably, memory or adaptive NK cells are an epigenetically-shaped long-living CD94/NKG2C+FcepsilonRIgamma- NK subpopulation identified in HCMV seropositive individuals, endowed with the enhanced ability to mediate CD16-dependent cytotoxicity and IFN-gamma production in response to opsonised target stimulation. Our recent data demonstrate the unique capability of anti-CD20 therapeutic mAbs to drive the selective in vitro expansion of memory NK cells, which maintain the phenotypic and functional signature of their freshly isolated counterpart.
Our project is aimed at studying the mechanistic basis of memory NK cell anti-tumor activity, that will allow their exploitation in adoptive therapy strategies to gain and sustain anti-tumor responses in therapeutic mAb-treated patients.
Main objectives:
1. To characterize the in vivo dynamics of memory NK cells in patients affected by B-cell chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), before and after anti-CD20 mAb-based regimens.
2. To characterize the molecular basis of tumor cell recognition, activation, and tissue homing profile of memory NK cells, as well as to set up GMP-compliant conditions for memory NK cell expansion.
3. To explore the ability of memory NK cells to favour dendritic cells (DCs) maturation finalysed to mAb-driven antitumor "vaccinal effect".