Identification of tumor-specific antigens recognized by human T cells

点击翻译按钮获取中文摘要

The aims of this research project are as follows. 1) to identify tumor-specific antigens strongly expressed in cancer tissues as compared with various normal tissues, 2) to investigate possible usefulness of these tumor antigens for diagnosis and treatment of cancers. In these five years of research period, we identified the following six tumor-specific antigens useful for the cancer diagnosis and/or therapy. 1) Glypican-3 (GPC3); GPC3 is an oncofetal antigen and a GPI-anchored membrane protein. GPC3 is strongly expressed in hepatocellular carcinoma (HCC) and melanoma, but not expressed in various normal adult tissues. The serum soluble GPC3 was detected in about 40% of patients with HCC as well as melanoma. It is worth to note that the patients with even early stage of these cancers were positive for serum GPC3. GPC3 peptide-specific and MHC class I-restricted CTLs could be generated by stimulation with GPC3 peptides of human peripheral blood mononuclear cells (PBMCs) in vitro or stim … More ulation of mice in vivo. The mice pre-immunized with bone marrow-derived dendritic cells (DCs) pulsed with the GPC3 peptides were protected from the growth of transplanted colon cancer cell line, C26 transfected with mouse GPC3, in a CD8^+ CTL-dependent manner. 2) Proliferation potential related protein (PP-RP); PP-RP is a nuclear protein co-localized with chromosome during mitosis. PP-RP is strongly expressed in esophageal cancer cells and moderate expression was observed in testis and placenta but not in many other normal tissues. Knock down of PP-RP gene expression by RNAi inhibited the cell proliferation of esophageal cancer cell line, and the strong expression of PP-RP correlated with poor prognosis of the patients. Human CTLs could be generated by stimulation of PBMCs with PP-RP-derived peptides and these CTLs killed esophageal cancer cell line both in vitro and in vivo in nude mice transplanted with human cancer cells. 3) KM-HN-1, HSP-105, CLP and KM-PA2 ; these antigens were identified by SEREX method using cancer patients sera and cDNA expression libraries established from cancer cells or testis. These antigens are strongly expressed in several types of cancer cells and in several normal tissues at a lower level. CTLs specific to peptides derived from these antigens were generated and they killed cancer cells in both human and mice. 4) Embryonic stem (ES) cell-derived DC vaccine; we succeeded in augmentation of anti-tumor immunity by immunization of mice with ES cell-derived DCs expressing simultaneously genes encoding for an antigen and chemokines. Less