TAP expression provides a general method for improving the recognition of malignant cells in vivo.
A major class of tumors lack expression of the transporters associated with antigen processing (TAP). These proteins are essential for delivery of antigenic peptides into the lumen of the endoplasmic reticulum (ER) and subsequent assembly with nascent major histocompatibility complex (MHC) class I, which results in cell surface presentation of the trimeric complex to cytolytic T lymphocytes. Cytolytic T lymphocytes are major effector cells in immunosurveillance against tumors. Here we have tested the hypothesis that TAP downregulation in tumors allows immunosubversion of this effector mechanism, by establishing a model system to examine the role of TAP in vivo in restoring antigen presentation, immune recognition, and effects on malignancy of the TAP-deficient small-cell lung carcinoma, CMT.64. To test the potential of providing exogenous TAP in cancer therapies, we constructed a vaccinia virus (VV) containing the TAP1 gene and examined whether VV-TAP1 could reduce tumors in mice. The results demonstrate that TAP should be considered for inclusion in cancer therapies, as it is likely to provide a general method for increasing immune responses against tumors regardless of the antigenic complement of the tumor or the MHC haplotypes of the host.
Alimonti
J
J
The Biotechnology Laboratory, Biomedical Research Centre, Department of Medical Genetics, Microbiology and Immunology, and Zoology, University of British Columbia, Vancouver, BC, Canada.
Zhang
Q J
QJ
Gabathuler
R
R
Reid
G
G
Chen
S S
SS
Jefferies
W A
WA
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000627:therapeutic use*; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000628:therapy*; D015395:Histocompatibility Antigens Class I; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D015166:Monitoring, Immunologic; D010641:Phenotype; D014162:Transfection
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse