Tumor-associated embryonic antigen-expressing vaccines that target CCR6 elicit potent CD8+ T cell-mediated protective and therapeutic antitumor immunity.
Despite its potency, the wider use of immunotherapy for B cell malignancies is hampered by the lack of well-defined tumor-specific Ags. In this study, we demonstrate that an evolutionarily conserved 37-kDa immature laminin receptor protein (OFA-iLRP), a nonimmunogenic embryonic Ag expressed by a variety of tumors, is rendered immunogenic if targeted to the APCs using the CCR6 ligands MIP3alpha/CCL20 and mDF2beta. The CCR6 targeting facilitated efficient Ag cross-presentation and induction of tumor-neutralizing CTLs. Although the Ag targeting alone, without activation of dendritic cells (DCs), is proposed to induce tolerance, and MIP3alpha does not directly activate DCs, the MIP3alpha-based vaccine efficiently induced protective and therapeutic antitumor responses. The responses were as strong as those elicited by the OFA-iLRP fusions with moieties that activated DCs and Th1-type cytokine responses, mDF2beta, or mycobacterial Hsp70 Ag. Although the same cDNA encodes the dimerized high-affinity mature 67-kDa mLRP that is expressed in normal tissues to stabilize the binding of laminin to cell surface integrins, the vaccines expressing OFA-iLRP elicited long-term protective CD8(+) T cell-mediated memory responses against syngeneic B cell lymphoma, indicating the potential application of these simple vaccines as preventive and therapeutic formulations for human use.
Biragyn
Arya
A
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. biragyna@mail.nih.gov
Schiavo
Roberta
R
Olkhanud
Purevdorj
P
Sumitomo
Kenya
K
King
Alan
A
McCain
Megan
M
Indig
Fred E
FE
Almanzar
Giovanni
G
Baatar
Dolgor
D
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000276:immunology; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D005260:Female; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D051379:Mice; D018613:Microscopy, Confocal; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000276:immunology*; D017474:Receptors, Laminin / Q000235:genetics / Q000276:immunology*; D014611:Vaccination
D000951:Antigens, Neoplasm; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D019496:Cancer Vaccines; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D017474:Receptors, Laminin; C031192:oncofetal antigens