Rituximab anti-CD20 mAb represents the front-line therapy for several B cell malignancies, and next-generation anti-CD20 mAbs, such as obinutuzumab, are approaching the clinical use. A poorly characterized aspect is the capability of mAb-based therapy to prime long-lasting anti-tumor T cell responses, the so-called "vaccinal effect", that may be highly relevant in mantaining long-term protection. 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, FcgRIIIA/CD16, represents one of the main mechanism by which therapeutic mAbs mediate their anti-tumor effects. Beside ADCC, CD16 ligation also results in cytokine production. In particular, NK-derived IFN-g is endowed with a well recognized role in the shaping of adaptive immune responses, and may represent a relevant factor in the vaccinal effect promoted by anti-tumor mAbs. Intriguingly, long-lived and highly functional populations of NK cells (dubbed "memory" NK cells) have been recently identified. Notably, such NK subset can be expanded in vitro by antibody-mediated recognition of virus-infected cells.
Our project will characterize the in vivo and in vitro dynamics of "memory" NK cells in response to therapeutic anti-CD20 mAb, and explore the potential of "memory" NK cells to drive anti-tumor adaptive responses.
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 phenotypic and functional profile of in vitro-expanded memory NK cells upon stimulation with rituximab or obinutuzumab anti-CD20 mAb.
3. To analyze the ability of "memory" NK cells to enhance DC maturation and antigen-presenting functions, to support their role in the "vaccinal effect" of therapeutic mAbs.
