Cross-linking a mAb to NKR-P2/NKG2D on dendritic cells induces their activation and maturation leading to enhanced anti-tumor immune response.
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 cell activation. We have recently reported the involvement of NKR-P2 in rat dendritic cell (DC) activation. We demonstrate the potential of agonistic anti-NKR-P2 mAb (1A6), which mimics the NKR-P2 ligand and induces activation and maturation of DCs. Interaction of DCs with 1A6 enhances nitric oxide-mediated apoptosis in tumor cells. Cross-linking of NKR-P2 with mAb1A6 up-regulates MHC II, CD86, CD1a, antigen-presentation function and decreases endocytic activity of DC, thus drives DCs to play a pivotal role in adaptive immune responses. NKR-P2 cross-linking with 1A6 also induced the secretion of inflammatory cytokines, IL-1beta, tumor necrosis factor-alpha, IFN-gamma and IL-12 by DCs. Blocking of 1A6-mediated activation and maturation with inhibitors of PI3K, p38K and ERK1/2K suggests involvement of MAP kinase in signal transduction. 1A6 cross-linking activates nuclear factor kappa B, which acts as key executioner of DC activation. Administration of 1A6 antibody induces rapid regression and protective immune responses against transplantable tumors, suggesting mAb induced activation and maturation of DCs, leading to enhanced anti-tumor immune response.
Srivastava
Raghvendra M
RM
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
Varalakshmi
Ch
Ch
Khar
Ashok
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000954:Antigens, Surface / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology*; D051940:B7-2 Antigen / Q000032:analysis / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007155:Immunologic Factors / Q000276:immunology; D018664:Interleukin-12 / Q000032:analysis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008114:Liver Neoplasms, Experimental / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009368:Neoplasm Transplantation / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D016328:NF-kappa B; D055655:NK Cell Lectin-Like Receptor Subfamily K; C113208:NKR-P2 protein, rat; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide