Immunization with tumor-associated epitopes fused to an endoplasmic reticulum translocation signal sequence affords protection against tumors with down-regulated expression of MHC and peptide transporters

• Published in: International immunology 2001-03, Vol.13 (3), p.265-271
• Main Authors: Sherritt, Martina, Cooper, Leanne, Moss, Denis J., Kienzle, Nobert, Altman, John, Khanna, Rajiv
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation - genetics; Antigens, Neoplasm - immunology; ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP Binding Cassette Transporter, Subfamily B, Member 3; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - physiology; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CTL cytotoxic T lymphocyte; CTLp precursor cytotoxic T lymphocytes; Cytotoxicity, Immunologic; DC dendritic cell; Endoplasmic Reticulum - metabolism; Epitopes - immunology; ER endoplasmic reticulum; H-2 Antigens - genetics; H-2 Antigens - immunology; Immunization; Immunologic Memory; Immunotherapy, Active - methods; LPS lipopolysaccharide; Melanoma, Experimental - immunology; Melanoma, Experimental - prevention & control; Melanoma, Experimental - therapy; Mice; OVA ovalbumin; PE phycoerythrin; Protein Sorting Signals - genetics; Protein Transport - genetics; Recombinant Fusion Proteins - immunology; T-Lymphocytes, Cytotoxic - immunology; TAE tumor-associated epitope; TRP tyrosinase-related protein; Vaccines, Synthetic - immunology; Vaccines, Synthetic - therapeutic use
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/13.3.265

Treatment of human cancers with an inherent antigen-processing defect due to a loss of peptide transporters (TAP-1 and TAP-2) and/or MHC class I antigen expression remains a considerable challenge. There is now an increasing realization that tumor cells with down-regulated expression of TAP and/or MHC class I antigens display strong resistance to cytotoxic T lymphocyte (CTL)-mediated immune control, and often fail to respond to the conventional immunotherapeutic protocols based on active immunization with tumor-associated epitopes (TAE) or adoptive transfer of tumor-specific T cells. In the present study, we describe a novel approach based on immunization with either genetically modified tumor cells or naked DNA vectors encoding TAE fused to an endoplasmic reticulum (ER) signal sequence (ER-TAE) which affords protection against challenge by melanoma cells with down-regulated expression of TAP-1/2 and MHC class I antigens. In contrast, animals immunized with a vaccine based on TAE alone showed no protection against tumor challenge. Although MHC–peptide tetramer analysis showed a similar frequency of antigen-specific CTL in both ER-TAE- and TAE-immunized mice, functional analysis revealed that CTL activated following immunization with ER-TAE displayed significantly higher avidity for TAE when compared to animals immunized with the TAE alone. These observations provide a new strategy in anti-cancer vaccine design that allows activation of a highly effective and well-defined CTL response against tumors with down-regulated expression of TAP and MHC class I antigens.