Genetic fusions with viral chemokines target delivery of nonimmunogenic antigen to trigger antitumor immunity independent of chemotaxis.
The ideal vaccine carrier should be able to target antigen delivery and possibly recruit antigen-presenting cells (APC) and deliver an activation signal to promote adaptive immune responses. Ligands for chemokine receptors expressed on APC may be attractive candidates, as they can both target and attract APC. To investigate the requirement for APC recruitment, we used a pair of viral chemokines, agonist herpes simplex virus 8-derived macrophage inflammatory protein-I (vMIP-I) and antagonist MC148, which induce and suppress chemotaxis, respectively. Chemokine-antigen fusions efficiently delivered a model nonimmunogenic tumor antigen to APC for processing and presentation to antigen-specific T cells in vitro. Physical linkage of chemokine and antigen and specific binding of chemokine receptor by the fusion protein were required. Mice immunized with vMIP-I or MC148 fusion DNA vaccines elicited protection against tumor challenge. Therefore, vaccine efficacy depends primarily on the ability of the carrier to target antigen delivery to APC for subsequent processing and presentation, and chemotaxis directly induced by the chemokine moiety in the fusion may not be necessary.
Ruffini
Pier Adelchi
PA
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Biragyn
Arya
A
Coscia
Marta
M
Harvey
Linda K
LK
Cha
Soung-Chul
SC
Bogen
Bjarne
B
Kwak
Larry W
LW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D003001:Cloning, Molecular; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D019444:Vaccines, DNA / Q000008:administration & dosage; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018925:Chemokines; D019742:Chemokines, CC; C435144:MC148 protein, poxvirus molluscum contagiosum; D019402:Macrophage Inflammatory Proteins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D014764:Viral Proteins; C108459:vMIP-1 protein, Human herpesvirus 8