Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway.
Sequence analyses of the transporter associated with antigen processing (TAP) in tumor cell lines with deficient MHC class I surface expression identified a bp deletion at position 1489 near the ATP-binding domain of Tap1, causing a frameshift in one melanoma cell line. The impaired TAP1 protein expression was associated with deficient TAP2 protein expression, peptide binding, translocation, and MHC class I surface expression. Stable TAP1 gene transfer reconstitutes the described defects, whereas lysis by HLA-A2-restricted CTLs was still abrogated. This was attributable to a 2-bp insertion at position 890 in the HLA-A2 gene and was corrected after HLA-A2 cotransfection. This study describes for the first time mutations in two distinct components of the MHC class I antigen processing pathway, suggesting an immune selection against CTLs recognizing both TAP-dependent and -independent T-cell epitopes.
Seliger
B
B
Johannes Gutenberg-University, Third Department of Internal Medicine, 55101 Mainz, Germany. B.Seliger@3-med.klinik.uni-mainz.de
Ritz
U
U
Abele
R
R
Bock
M
M
Tampé
R
R
Sutter
G
G
Drexler
I
I
Huber
C
C
Ferrone
S
S
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015789:HLA-A2 Antigen; C073119:TAP1 protein, human; C071692:TAP2 protein, human