Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants

• Published in: Nature medicine Vol. 12; no. 4; pp. 417 - 424
• Main Authors: van Hall, Thorbald, Wolpert, Elisabeth Z, van Veelen, Peter, Laban, Sandra, van der Veer, Michael, Roseboom, Marjet, Bres, Sandra, Grufman, Per, de Ru, Arnoud, Meiring, Hugo, de Jong, Ad, Franken, Kees, Teixeira, Antoinette, Valentijn, Rob, Drijfhout, Jan Wouter, Koning, Frits, Camps, Marcel, Ossendorp, Ferry, Kärre, Klas, Ljunggren, Hans-Gustaf, Melief, Cornelis J M, Offringa, Rienk
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-04-2006
• Subjects: Animals; Antigen Presentation; Antiporters - deficiency; Antiporters - genetics; Antiporters - physiology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cellular biology; Clone Cells; Cytotoxicity Tests, Immunologic; Epitopes; Gene expression; Gene Targeting; Genes, MHC Class I; Genetic Variation; Histocompatibility Antigens Class I - immunology; Immune system; Immunoglobulins - deficiency; Immunoglobulins - genetics; Immunoglobulins - physiology; Immunologic Surveillance; Immunotherapy; Immunotherapy, Adoptive; Lymphocytes; Medicin och hälsovetenskap; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Molecular Sequence Data; Peptides; Proteins; T-Lymphocytes, Cytotoxic - immunology; Tumor Escape; Tumors; Vaccines, Synthetic - therapeutic use
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1381

Defects in major histocompatibility complex (MHC) class I-restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.