Identification of Cyclin B1 as a Shared Human Epithelial Tumor-Associated Antigen Recognized by T Cells

Abstract

We eluted peptides from class I molecules of HLA-A2.1+ breast adenocarcinoma and loaded reverse phase high-performance liquid chromatography (HPLC) fractions onto dendritic cells to prime naive CD8+ T cells. Fractions that supported growth of tumor-specific cytotoxic T lymphocytes were analyzed by nano-HPLC micro-ESI tandem mass spectrometry. Six HLA-A2.1-binding peptides, four 9-mers (P1-P4) differing in the COOH-terminal residue, and two 10-mers (P5 and P6) with an additional COOH-terminal alanine, were identified in one fraction. Peptide sequences were homologous to cyclin B1. We primed CD8+ T cells from another HLA-A2.1+ healthy donor with synthetic peptides and generated P4-specific responses. We also detected memory T cells specific for one or more of these peptides in patients with breast cancer and squamous cell carcinomas of the head and neck (SCCHN). T cells from one patient, restimulated once in vitro, could kill the tumor cell line from which the peptides were derived. Immunohistochemical analysis of tumor lines and tissue sections showed cyclin B1 overexpression and aberrant localization in the cytoplasm instead of the nucleus. Sequencing genomic DNA and cDNA corresponding to P1–P6 region showed that differences in COOH-terminal residues were not due to either DNA mutations or errors in transcription, suggesting a high error rate in translation of cyclin B1 protein in tumors.

Antibody detection using tumor-associated antigen mini-array in immunodiagnosing human hepatocellular carcinoma

“…Autoantibodies to p53 in cancer were first reported in 1982 [7] and since then there have been numerous reports confirming and extending this finding [reviewed in 8]. The mechanism underlying the production of such autoantibodies are not completely understood but the available data show that many of the target antigens are cellular proteins whose aberrant regulation could lead to tumorigenesis, such as p53 [8], HER-2/neu and ras [9,10], or are proteins whose dysregulation could have tumorigenic potential including mRNA binding proteins such as p62 [5] and cell-cycle control proteins such as cyclin B1 [11,12]. In the case of p62 which is primarily expressed in fetal tissues and is absent in adult tissues, immunogenicity appears to be related to abnormal expression of p62 in tumor cells [13].…”

Cloning of B cell lymphoma-associated antigens using modified phage-displayed expression cDNA library and immunized patient sera

“…Particularly, the importance of CD8 + and CD4 + T cells in the inhibition of tumor growth and eradication of cancer cells has been emphasized (Rosenberg, 2001;Wang, 2001). Tumor-associated antigens (TAA) are defined as a product of genes preferentially expressed in malignant cells, such as cancer testis antigens (CT) (Jager et al, 1998), or antigens derived from mutated (Brandle et al, 1996;Mandruzzato et al, 1997), improperly processed and regulated genes (Kao et al, 2001). At present, a number of TAAs have been identified, although methods for identifying clinically relevant, rejection antigens are needed.…”

The shared tumor associated antigen cyclin‐A2 is recognized by high‐avidity T‐cells

“…MHC-class I binding peptides have been identified that stimulate CTL from cancer patients. 32,36 In view of these encouraging results, an increasing number of studies is currently addressing the role of the cyclins as tumor antigens in immuno surveillance and immunotherapy. 2 We conclude that the induction of MHC-restricted CTL specific for the peptide CA213is feasible and that such CTL can recognize endogenously expressed antigen on tumor cells.…”