Cyclin-dependent kinaselike 5 is a novel target of immunotherapy in adult T-cell leukemia.
In the present study, we attempted a comprehensive analysis of human leukocyte antigen (HLA) class I-bound peptides presented on adult T-cell leukemia (ATL) cells by the latest technology of mass spectrometry combined with reversed phase liquid chromatography (LC/MS) to identify novel tumor-associated antigens. We screened the sequenced peptides for those compatible with the motives of the respective HLA class I alleles. Then, we narrowed down the candidate peptides according to the differential expression of their source proteins between ATL cells and normal CD4 T cells. Among these candidates, we focused on cyclin-dependent kinaselike 5 (CDKL5) because it was highly expressed in several ATL cell lines and some ATL clinical samples but not in normal CD4 T cells. To examine its immunogenicity, we stimulated CD8 T cells from an HLA-B62 healthy donor several times with autologous monocyte-derived dendritic cells loaded with HLA-B*62-restricted CDKL5 peptide1012-1021 QVNQAALLTY that we identified. CDKL5-stimulated bulk CD8 T cells exerted higher cytotoxicity against CDKL5 peptide-loaded autologous Epstein Barr virus-transformed B cell line (LCL) than against unloaded LCL. Furthermore these T cells had strong cytotoxic activity against HLA-B*62-positive CDKL5-positive but not HLA-B*62-negative CDKL5-positive ATL cells. These results demonstrate that CDKL5 is a novel tumor (leukemia) antigen in ATL and that the HLA-B*62-restricted CDKL5 peptide can be used for cytotoxic T-lymphocyte-mediated immunotherapy. Identification of tumor-associated antigens by LC/MS is an eligible and efficient method suitable for future taylor-made immunotherapy of hematologic malignancies.
Kawahara
Masahiro
M
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo, Kyoto 606-8507, Japan.
Hori
Toshiyuki
T
Matsubara
Yasushi
Y
Okawa
Katsuya
K
Uchiyama
Takashi
T
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D001402:B-Lymphocytes; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy; D013058:Mass Spectrometry; D009842:Oligopeptides / Q000276:immunology; D010455:Peptides / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000276:immunology*
D000951:Antigens, Neoplasm; D015235:HLA-B Antigens; D015395:Histocompatibility Antigens Class I; D009842:Oligopeptides; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human