title: TAP expression level in tumor cells defines the nature and processing of MHC class I peptides for recognition by tumor-specific cytotoxic T lymphocytes.
abstract: We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT(16-25) is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT(16-25) epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-γ treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT(16-25) human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8(+) T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy.
authors.affiliation: Chimie et Sciences de la Vie et de la Terre, Université Saint-Esprit de Kaslik, Jounieh, Lebanon.
authors.forename: Faten
authors.initials: F
authors.lastname: El Hage
authors.forename: Aurélie
authors.initials: A
authors.lastname: Durgeau
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D017951:Antigen Presentation / Q000235:genetics*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002116:Calcitonin / Q000737:chemistry / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D018528:ATP-Binding Cassette Transporters; D018984:Epitopes, T-Lymphocyte; D011498:Protein Precursors; C477327:transporter associated with antigen processing (TAP); C033183:preprocalcitonin; D002116:Calcitonin