CROSSLINKING A MONOCLONAL ANTIBODY TO NKR- P2/NKG2D ON DENDRITIC CELLS INDUCES THEIR ACTIVATION AND MATURATION LEADING TO ENHANCED ANTITUMOR IMMUNE RESPONSE

摘要

Monoclonal antibody mediated therapy is a promising area of anticancer research. Agonistic monoclonal enhances immune responses to suppress cancer growth by stimulating specific receptor on immune cells. NKR-P2/NKG2D is the chief tumor recognition receptor of NK cells and some T cells, which recognizes stress inducible ligands on tumors and mediates immune cell activation. We have recently reported involvement of NKR-P2 in dendritic cell activation. We show the potential of agonistic anti-NKRP2 mAb (1A6), which mimics the NKR-P2 ligand and induces activation and maturation of DCs. Interaction of DCs with 1A6, enhances NO mediated apoptosis in tumor cells. Crosslinking of NKR-P2 with mAblA6 upregulates MHC-II, CD86, CDla, antigen presentation function, and decreases endocytic activity of DC, thus drives DCs to play a pivotal role in adaptive immune responses. NKR-P2 crosslinking with 1A6 also induced the secretion of inflammatory cytokines, IL-1beta, TNF-a, DFNy and IL-12 by dendritic cells. Blocking of 1A6 mediated activation and maturation with inhibitors of PI3K, p38K and ERK1/2K suggests involvement of MAP kinase in signal transduction. 1A6 crosslinking activates NFkB, which acts as key executioner of DC activation. Administration of 1A6 induces rapid regression of transplanted tumors (solid/ascites) suggesting mAb-induced activation and maturation of DCs, leading to enhanced antitumor immune response. Theses results provide optimism that is required for the therapeutic mAbs, which binds specific target and exploits novel mechanism to cure various type of tumor.