title: MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer.
abstract: Cancer cells display novel phosphopeptides in association with MHC class I and II molecules. In this study, we evaluated two HLA-A2-restricted phosphopeptides derived from the insulin receptor substrate (IRS)-2 and the cell-cycle regulator CDC25b. These proteins are both broadly expressed in multiple malignancies and linked to cancer cell survival. Two phosphopeptides, termed pIRS-21097-1105 and pCDC25b38-46, served as targets of strong and specific CD8 T-cell memory responses in normal human donors. We cloned T-cell receptor (TCR) cDNAs from murine CD8 T-cell lines specific for either pIRS-21097-1105 or pCDC25b38-46. Expression of these TCRs in human CD8 T cells imparted high-avidity phosphopeptide-specific recognition and cytotoxic and cytokine-secreting effector activities. Using these cells, we found that endogenously processed pIRS-21097-1105 was presented on HLA-A2(+) melanomas and breast, ovarian, and colorectal carcinomas. Presentation was correlated with the level of the Ser(1100)-phosphorylated IRS-2 protein in metastatic melanoma tissues. The highest expression of this protein was evident on dividing malignant cells. Presentation of endogenously processed pCDC25b38-46 was narrower, but still evident on HLA-A2(+) melanoma, breast carcinoma, and lymphoblastoid cells. Notably, pIRS-21097-1105-specific and pCDC25b38-46-specific TCR-expressing human CD8 T cells markedly slowed tumor outgrowth in vivo. Our results define two new antigens that may be developed as immunotherapeutic agents for a broad range of HLA-A2(+) cancers.
authors.affiliation: Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Zarling
authors.affiliation: Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Obeng
authors.affiliation: Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: A Nicole
authors.initials: AN
authors.lastname: Desch
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia. Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia.
authors.forename: Joel
authors.initials: J
authors.lastname: Pinczewski
authors.affiliation: Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Cummings
authors.affiliation: Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia. Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Deacon
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Mark
authors.initials: M
authors.lastname: Conaway
authors.affiliation: Human Immune Therapy Center, University of Virginia, Charlottesville, Virginia. Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.affiliation: Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia. vhe@virginia.edu.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D010748:Phosphopeptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; D010748:Phosphopeptides; D011948:Receptors, Antigen, T-Cell; D020687:cdc25 Phosphatases