Abstract
The major histocompatibility complex (MHC) peptide repertoire of cancer cells serves both as a source for new tumor antigens for development of cancer immunotherapy and as a rich information resource about the protein content of the cancer cells (their proteome). Thousands of different MHC peptides are normally displayed by each cell, where most of them are derived from different proteins and thus represent most of the cellular proteome. However, in contrast to standard proteomics, which surveys the cellular protein contents, analyses of the MHC peptide repertoire correspond more to the rapidly degrading proteins in the cells (i.e. the transient proteome). MHC peptides can be efficiently purified by affinity chromatography from membranal MHC molecules, or preferably following transfection of vectors for expression of recombinant soluble MHC molecules. The purified peptides are resolved and analyzed by capillary high-pressure liquid chromatography-electrospray ionization-tandem mass spectrometry, and the data are deciphered with new software tools enabling the creation of large databanks of MHC peptides displayed by different cell types and by different MHC haplotypes. These lists of identified MHC peptides can now be used for searching new tumor antigens, and for identification of proteins whose rapid degradation is significant to cancer progression and metastasis. These lists can also be used for identification of new proteins of yet unknown function that are not detected by standard proteomics approaches. This review focuses on the presentation, identification and analysis of MHC peptides significant for cancer immunotherapy. It is also concerned with the aspects of human proteomics observed through large-scale analyses of MHC peptides.
Highlights
The major histocompatibility complex (MHC) peptide repertoire of cancer cells serves both as a source for new tumor antigens for development of cancer immunotherapy and as a rich information resource about the protein content of the cancer cells
MHC class I molecules are loaded in the endoplasmic reticulum (ER) with peptides derived from proteasomal proteolysis of both normal and pathogenic proteins, most of which are 8 –10 amino acids long
The MHC molecules are shuttled to the cell surface with their peptide cargo, which are presented for scrutiny by CD8ϩ T lymphocytes through their T cell receptor (TCR)
Summary
Research on tumor immunology aims on one hand to find ways to exploit the capacity of the immune system to kill tumor cells (immunotherapy) and on the other hand to identify new tumor markers for diagnostics, prognostics, or as targeting molecules. Tumor-associated antigens (TAA) are proteins that are not unique to cancer cells but are expressed to a larger extent in tumor relative to normal cells, some of which are potentially useful for immunotherapy. TAA include cancer testis antigens, which are proteins normally expressed in immune-privileged tissues (such as testis and placenta) and differentiation antigens, which are normally expressed in nonessential tissues (such as prostate, ovaries, and melanocytes). Both cancer testis antigens and differentiation antigens were extensively tested for their immunotherapeutic potential, and some of them have been shown to induce powerful response with measurable benefit to the patients (20). It was suggested that the preferred time for immunotherapy is at the minimal residual disease stage, because micro-metastases are expected to be more responsive than large tumors with their immune suppressing microenvironment (21, 22, reviewed in Ref. 23)
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