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Induction of Antitumor Immunity by CTL Epitopes Genetically Linked to Membrane-Anchored ₂-Microglobulin¹

Alon Margalit^2,*,, Helena M. Sheikhet^2,, Yaron Carmi^3,*, Dikla Berko^4,*, Esther Tzehoval, Lea Eisenbach and Gideon Gross^5,*,

^* Laboratory of Immunology, MIGAL-Galilee Technology Center, Kiryat Shmona, Israel; Department of Biotechnology, Tel-Hai Academic College, Upper Galilee, Israel; and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Level and persistence of antigenic peptides presented by APCs on MHC class I (MHC-I) molecules influence the magnitude and quality of the ensuing CTL response. We recently demonstrated the unique immunological properties conferred on APCs by expressing ₂-microglobulin (₂m) as an integral membrane protein. In this study, we explored membrane-anchored ₂m as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. We expressed in mouse RMA-S cells two H-2K^b binding peptides from MO5, OVA_257–264, and TRP-2_181–188, each genetically fused with the N terminus of membranal ₂m via a short linker. Specific Ab staining and T cell hybridoma activation confirmed that OVA_257–264 was properly situated in the MHC-I binding groove. In vivo, transfectants expressing both peptides elicited stronger CTLs and conferred better protection against MO5 than peptide-saturated RMA-S cells. Cells expressing OVA_257–264/₂m were significantly superior to OVA_257–264-charged cells in their ability to inhibit the growth of pre-established MO5 tumors. Our results highlight the immunotherapeutic potential of membranal ₂m as a universal scaffold for optimizing Ag presentation by MHC-I molecules.