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.
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.
Sherritt
M
M
Tumour Immunology Laboratory, Epstein-Barr Virus Unit, Queensland Institute of Medical Research and University of Queensland Joint Oncology Program, Bancroft Centre, 300 Herston Road, Brisbane, Queensland 4029, Australia.
Cooper
L
L
Moss
D J
DJ
Kienzle
N
N
Altman
J
J
Khanna
R
R
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D007114:Immunization; D007156:Immunologic Memory; D016233:Immunotherapy, Active / Q000379:methods*; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D021382:Protein Sorting Signals / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D006183:H-2 Antigens; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D014614:Vaccines, Synthetic; C071692:TAP2 protein, human