title: Novel natural immunogenic peptides from Numb1 and Notch1 proteins for CD8+ cells in ovarian ascites.
abstract: Notch is a plasma membrane receptor involved in the control of cell fate specification and in the maintenance of the balance between proliferation and differentiation in many cell lineages. Disruption of Notch has been implicated in a variety of hematological and solid cancers. Numb is also expressed in many adult mammalian cells. Adult cells divide symmetrically, and Numb is symmetrically partitioned at mitosis. The Numb-mediated regulation of Notch is believed to play a causative role in naturally occurring breast cancers. Reduction of Numb levels in breast tumors is regulated by proteasomal degradation. We reasoned that if the disregulated negative control of Notch by Numb protein is the consequence of Numb proteasomal degradation, then degradation of Numb can generate peptides which are transported, presented by MHC-I molecules. Surprisingly we found few candidate naturally processed peptides from Notch1, Notch2, and Numb1. CD8+ T cells expressing TCRs which specifically recognized peptides Notch1 (2112-2120) and Numb1 (87-95) were presented in the ascites of ovarian cancer patients. Many of these cells were differentiated and expressed high levels of Perforin. The natural immunogenicity of Notch1 and particularly of Numb1 suggests a mechanism of immunosurveillance which is overcome during tumor progression. Immunotherapy with tumor antigens from Notch and Numb should be important for treatment of cancer patients.
authors.affiliation: Department of Gynecologic Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishiyama
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsueda
authors.forename: Lovell A
authors.initials: LA
authors.lastname: Jones
authors.forename: Clay
authors.initials: C
authors.lastname: Efferson
authors.forename: Joseph
authors.initials: J
authors.lastname: Celestino
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Ioannides
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuda
authors.forename: David Z
authors.initials: DZ
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D001201:Ascites / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D019281:Dimerization; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011487:Protein Conformation; D051881:Receptor, Notch1 / Q000737:chemistry / Q000276:immunology*
chemical_list: D015789:HLA-A2 Antigen; D007074:Immunoglobulin G; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D010455:Peptides; D051881:Receptor, Notch1; D046988:Proteasome Endopeptidase Complex