Natural Killer (NK) cell-mediated effector functions significantly contribute to anti-tumor activity of tumor-targeting monoclonal antibodies (mAbs): indeed, FcgammaRIIIa (CD16) aggregation by means of opsonized targets not only triggers tumor cell killing but may also favor 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 cytomegalovirus (HCMV) seropositive individuals, endowed with the enhanced ability to mediate CD16-dependent cytotoxicity and IFN-gamma production in response to opsonized target stimulation. Our recent data demonstrate the unique capability of tumor-targeting 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 Her2+ Breast Cancer (BC) patients before and after trastuzumab-based regimens in neoadjuvant setting.
2. To set up trastuzumab-driven memory NK cell expansion conditions, and to characterize the molecular basis of their tumor cell recognition, activation, metabolic and tissue homing profile, as well as their immune checkpoint sensitivity.
3. To explore the ability of memory NK cells to support dendritic cells (DCs) maturation and the subsequent development of anti-tumor specific cytotoxic responses.
Despite the unprecedented success of anti-Her2 mAb, a proportion of patients still fails to respond to, or more commonly relapses, after receiving chemoimmunotherapy, and the promotion of an endogenous long-lasting anti-tumor immune response in mAb-treated patients is becoming a major goal for improving the efficacy of mAb-based therapies.
The ex vivo and in vitro characterization of the phenotypic and functional profile of memory NK cells in therapeutic mAb-treated BC patients has several major implications: 1. to elucidate a novel mechanism of NK cell memory generation driven by CD16 (FcgammaRIIIa) in a therapeutic setting; 2. to provide a mechanistic explanation for the ability of NK cells to support the generation of an anti-tumor vaccinal effect in response to mAb treatment; 3. to provide an experimental framework for the rational design of combination therapy protocols aimed at optimizing the efficacy of therapeutic mAb, and at enhancing the anti-tumor activity of NK cells.
We strongly believe that the results of this research project will uncover previously unrecognized mechanisms of NK cell plasticity and provide information with a strong translational potential. The characterization of memory NK cells ability to affect DC maturation and functions will be instrumental for the design of anti-tumor mAb-based therapies able to more effectively promote the development of long-term adaptive responses in cancer patients. Further, taking into account that the poor in vivo survival and the lack of specificity of NK cells have limited their use in adoptive therapy strategies, the definition of the phenotypic and functional profile of a long-lived NK cell population with powerful anti-cancer skills, will be instrumental for the better exploitation of NK cells for the ultimate benefit of treating cancer patients.