Journal
TRANSLATIONAL IMMUNOLOGY IN ASIA-OCEANIA
Volume 1283, Issue -, Pages 75-80Publisher
BLACKWELL SCIENCE PUBL
DOI: 10.1111/j.1749-6632.2012.06777.x
Keywords
lung cancer; tumor-associated antigens; cytotoxic T lymphocytes; antigen processing
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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)-gamma 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.
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