Different expression levels of the TAP peptide transporter lead to recognition of different antigenic peptides by tumor-specific CTL.
Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT(16-25) is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8(+) T cell immunity.
INSERM U753, Team 1, Tumor Antigens and CTL Reactivity, Integrated Research Cancer Institute in Villejuif, Gustave Roussy Institute, 94805 Villejuif Cedex, France.
Aurélie
A
Durgeau
Faten
F
El Hage
Isabelle
I
Vergnon
Pierre
P
Validire
Vincent
V
de Montpréville
Benjamin
B
Besse
Jean-Charles
JC
Soria
Thorbald
T
van Hall
Fathia
F
Mami-Chouaib
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*
D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; C477327:transporter associated with antigen processing (TAP)