Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens.
Chemokine receptors are differentially expressed on immature and mature dendritic cells (DC). Herein, we demonstrate for the first time that murine antimicrobial peptides beta-defensins 2 and 3 bind murine CCR6, similarly to inflammatory chemokine macrophage-inflammatory protein 3alpha, and they chemoattract bone marrow-derived immature, but not mature DC. Using various chemokines or defensins fused with nonimmunogenic tumor Ags, we studied their capacity to delivery Ags to subsets of immune cells to elicit antitumor immunity. We demonstrate that DNA immunizations with fusion constructs with beta-defensin 2 or inflammatory chemokines that target immature DC, but not homeostatic chemokines secondary lymphoid tissue chemokine, CCL21, or stromal cell-derived factor 1, CXCL12, which chemoattract mature DC, elicit humoral, protective, and therapeutic immunity against two different syngeneic lymphomas.
Biragyn
A
A
Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA. arya@mail.ncifcrf.gov
Surenhu
M
M
Yang
D
D
Ruffini
P A
PA
Haines
B A
BA
Klyushnenkova
E
E
Oppenheim
J J
JJ
Kwak
L W
LW
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D019707:Receptors, Chemokine / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000502:physiology; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D023083:beta-Defensins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology
D000888:Antibodies, Anti-Idiotypic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018925:Chemokines; D007135:Immunoglobulin Variable Region; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D023083:beta-Defensins