Preprocalcitonin signal peptide generates a cytotoxic T lymphocyte-defined tumor epitope processed by a proteasome-independent pathway.
We identified an antigen recognized on a human non-small-cell lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide is presented by HLA-A2 and is encoded by the CALCA gene, which codes for calcitonin and for the alpha-calcitonin gene-related peptide. The peptide is derived from the carboxy-terminal region of the preprocalcitonin signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing. Processing occurs within the endoplasmic reticulum of all tumoral and normal cells tested, including dendritic cells, and it involves signal peptidase and the aspartic protease, signal peptide peptidase. The CALCA gene is overexpressed in medullary thyroid carcinomas and in several lung carcinomas compared with normal tissues, leading to recognition by the T cell clone. This new epitope is, therefore, a promising candidate for cancer immunotherapy.
El Hage
Faten
F
Institut National de la Santé et de la Recherche Médicale, Unité 753, Laboratoire Immunologie des Tumeurs Humaines, Villejuif, France.
Stroobant
Vincent
V
Vergnon
Isabelle
I
Baurain
Jean-François
JF
Echchakir
Hamid
H
Lazar
Vladimir
V
Chouaib
Salem
S
Coulie
Pierre G
PG
Mami-Chouaib
Fathia
F
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002116:Calcitonin / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; C000606589:CALCA protein, human; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D015789:HLA-A2 Antigen; D011498:Protein Precursors; D021382:Protein Sorting Signals; D034741:RNA, Small Interfering; D002116:Calcitonin; D046988:Proteasome Endopeptidase Complex; D015740:Calcitonin Gene-Related Peptide