Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell,CD4+ and CD8+ T cell epitopes |
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Authors: | Ilham Bettahi Gargi Dasgupta Olivier Renaudet Aziz Alami Chentoufi Xiuli Zhang Dale Carpenter Susan Yoon Pascal Dumy Lbachir BenMohamed |
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Affiliation: | (1) Laboratory of Cellular and Molecular Immunology, The Gavin S. Herbert Eye Institute, University of California Irvine, College of Medicine, Bldg. 55, Room 202, Irvine, Orange, CA 92868, USA;(2) Département de Chimie Moléculaire, UMR-CNRS 5250, ICMG FR 2607, Universite Joseph Fourier, 38041 Grenoble Cedex 9, France;(3) Center for Immunology, University of California Irvine, Irvine, CA 92697-1450, USA |
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Abstract: | Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants. In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing a chimeric peptide made of a CD8+ T cell epitope, from ovalbumin (OVA257–264) and an universal CD4+ T helper (Th) epitope (PADRE). The resulting CTL–Th peptide backbones was coupled to a carbohydrate B cell epitope based on a regioselectively addressable functionalized templates (RAFT), made of four α-GalNAc molecules at C-terminal. The N terminus of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA257–264-specific IFN-γ producing CD8+ T cells; (3) PADRE-specific CD4+ T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B Cell, CD4+, and CD8+ T cell epitopes-based immunotherapeutic cancer vaccines. Both I. Bettahi and G. Dasgupta have contributed equally to this work. |
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Keywords: | Vaccine Carbohydrate Glyco-lipopeptide CD4+ T cell CD8+ T cell |
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