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Tumor-Associated Embryonic Antigen-Expressing Vaccines that Target CCR6 Elicit Potent CD8⁺ T Cell-Mediated Protective and Therapeutic Antitumor Immunity¹

Arya Biragyn^2,*, Roberta Schiavo^3,*, Purevdorj Olkhanud^*, Kenya Sumitomo^*, Alan King, Megan McCain, Fred E. Indig, Giovanni Almanzar^* and Dolgor Baatar^*

^* Laboratory of Immunology and Research Resources Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224; and Cyto Pulse Sciences, Glen Burnie, MD 21061

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 MIP3/CCL20 and mDF2. 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 MIP3 does not directly activate DCs, the MIP3-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, mDF2, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.

² Address correspondence and reprint requests to Dr. Arya Biragyn, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 21, Baltimore, MD 21224. E-mail address: biragyna{at}mail.nih.gov

³ Current address: Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy.

⁴ Abbreviations used in this paper: TAA, tumor-associated Ag; Id, idiotypic Ab; OFA, oncofetal Ag; OFA-iLRP, OFA-immature laminin receptor 37-kDa protein; DC, dendritic cells; MHC-I, MHC class I; iDC, immature DC; mDF2, murine -defensin 2.

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