Tumor Antigens and Proteomics from the Point of View of the Major Histocompatibility Complex Peptides

Admon, Arie; Barnea, Eilon; Ziv, Tamar

doi:10.1074/mcp.r300004-mcp200

Cited by 44 publications

(38 citation statements)

References 72 publications

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“…Methodologies used to discover class I MHC-restricted antigens displayed selectively on cancer cells frequently involve identification of the peptide target recognized by an already characterized T lymphocyte (30). Another approach relies on the ability to identify candidate source proteins, usually based on selective expression or overexpression and on the use of predictive algorithms to identify appropriate peptide sequences.…”

Section: Resultsmentioning

confidence: 99%

“…Mice expressing a transgenic recombinant HLA-A*0201 molecule (AAD) were immunized with activated bone-marrow-derived dendritic cells pulsed with either phosphorylated IRS2 (pIRS2 1097-1105 ), phosphorylated ␤-catenin (p␤-catenin [30][31][32][33][34][35][36][37][38][39] ), or phosphorylated CDC25b (pCDC25b 38-46 ) peptides. Three weeks later, CD8 ϩ T lymphocytes were isolated and cultured in vitro in the presence of irradiated splenocytes pulsed with the same phosphopeptides (11).…”

Section: Resultsmentioning

confidence: 99%

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Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy

Zarling

Polefrone

Evans

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

167

217

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Alterations in phosphorylation of cellular proteins are a hallmark of malignant transformation. Degradation of these phosphoproteins could generate cancer-specific class I MHC-associated phosphopeptides recognizable by CD8 ؉ T lymphocytes. In a comparative analysis of phosphopeptides presented on the surface of melanoma, ovarian carcinoma, and B lymphoblastoid cells, we find 5 of 36 that are restricted to the solid tumors and common to both cancers. Differential presentation of these peptides can result from differential phosphorylation of the source proteins. Recognition of the peptides on cancer cells by phosphopeptide-specific CD8 ؉ T lymphocytes validates the potential of these phosphopeptides as immunotherapeutic targets.tandem mass spectrometry ͉ immobilized metal-affinity chromatography

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy

Zarling

Polefrone

Evans

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

167

217

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“…The peptides are recovered from immunoaffinity purified MHC molecules after detergent solubilization of the cells (40,41), from soluble MHC molecules secreted to the cells' growth medium (42,43) or from patients' plasma (44). The purified peptides pools are resolved by capillary chromatography and the individual peptides are identified and quantified by tandem mass spectrometry (40), (reviewed in (45)(46)(47)). In cultured cells, quantitative analysis can also be followed by metabolic incorporation of stable isotope labeled amino acids (SILAC) (48).…”

mentioning

confidence: 99%

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

Milner

Gutter-Kapon

Bassani-Strenberg

et al. 2013

Molecular & Cellular Proteomics

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The Major histocompatibility complex (MHC) class I peptidome is thought to be generated mostly through proteasomal degradation of cellular proteins, a notion that is based on the alterations in presentation of selected peptides following proteasome inhibition. We evaluated the effects of proteasome inhibitors, epoxomicin and bortezomib, on human cultured cancer cells. Because the inhibitors did not reduce the level of presentation of the cell surface human leukocyte antigen (HLA) molecules, we followed their effects on the rates of synthesis of both HLA peptidome and proteome of the cells, using dynamic stable isotope labeling in tissue culture (dynamic-SILAC). The inhibitors reduced the rates of synthesis of most cellular proteins and HLA peptides, yet the synthesis rates of some of the proteins and HLA peptides was not decreased by the inhibitors and of some even increased. Therefore, we concluded that the inhibitors affected the production of the HLA peptidome in a complex manner, including modulation of the synthesis rates of the source proteins of the HLA peptides, in addition to their effect on their degradation. The collected data may suggest that the current reliance on proteasome inhibition may overestimate the centrality of the proteasome in the generation of the MHC peptidome. It is therefore suggested that the relative contribution of the proteasomal and nonproteasomal pathways to the production of the MHC peptidome should be revaluated in accordance with the inhibitors effects on the synthesis rates of the source proteins of the MHC peptides. Molecular & Cellular Proteomics 12:

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“…These HLA peptidomes include a diversity of peptides, derived from both normal and abnormal proteins expressed in the cells. Thus, the HLA peptidomes were studied mostly in order to identify cancer specific peptides, for development of tumor immunotherapeutics (6,7) and as a source of information about the protein synthesis and degradation schemes within the cancer cells (8).…”

mentioning

confidence: 99%

Soluble plasma HLA peptidome as a potential source for cancer biomarkers

Bassani-Sternberg

Barnea

Beer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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120

133

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The HLA molecules are membrane-bound transporters that carry peptides from the cytoplasm to the cell surface for surveillance by circulating T lymphocytes. Although low levels of soluble HLA molecules (sHLA) are normally released into the blood, many types of tumor cells release larger amounts of these sHLA molecules, presumably to counter immune surveillance by T cells. Here we demonstrate that these sHLA molecules are still bound with their authentic peptide repertoires, similar to those of the membranal HLA molecules (mHLA). Therefore, a single immunoaffinity purification of the plasma sHLA molecules, starting with a few milliliters of patients' blood, allows for identification of very large sHLA peptidomes by mass spectrometry, forming a foundation for development of a simple and universal blood-based cancer diagnosis. The new methodology was validated using plasma and tumor cells of multiple-myeloma and leukemia patients, plasma of healthy controls, and with cultured cancer cells. The analyses identified thousands of sHLA peptides, including some cancer-related peptides, present among the sHLA peptidomes of the cancer patients. Furthermore, because the HLA peptides are the degradation products of the cellular proteins, this sHLA peptidomics approach opens the way for investigation of the patterns of protein synthesis and degradation within the tumor cells.

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Tumor Antigens and Proteomics from the Point of View of the Major Histocompatibility Complex Peptides

Cited by 44 publications

References 72 publications

Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy

Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

Soluble plasma HLA peptidome as a potential source for cancer biomarkers

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