title: Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.
abstract: Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC 28223, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Schettini
authors.forename: Amritha
authors.initials: A
authors.lastname: Kidiyoor
authors.forename: Dahlia M
authors.initials: DM
authors.lastname: Besmer
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Tinder
authors.forename: Lopamudra Das
authors.initials: LD
authors.lastname: Roy
authors.forename: Joseph
authors.initials: J
authors.lastname: Lustgarten
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000276:immunology*; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D054353:Perforin / Q000096:biosynthesis / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; C060192:MUC1 protein, human; D018396:Mucin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D054353:Perforin