Identification of tumor-specific antigens recognized by human T cells

人类 T 细胞识别的肿瘤特异性抗原的鉴定

• 批准号: 12213111
• 负责人: NISHIMURA Yasuharu
• 金额: $ 33.41万
• 依托单位: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213111/
• 关键词: Tumor-specific antigens; Tumor markers; Anti-tumor immunity; Cytotoxic T lymphocytes; Antigenic epitopes; cDNA microarray analysis; Serex method; Hepatocellular carcinoma; Melanoma (CONTINUE TO NEXT PAGE); 腫瘍抗原; 細胞障害性T細胞; ヘルパーT細胞; T細胞エピトープ; S

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

本研究项目的目的如下。1)鉴定与各种正常组织相比在癌组织中强表达的肿瘤特异性抗原，2）研究这些肿瘤抗原用于诊断和治疗癌症的可能有用性。在这五年的研究期间，我们鉴定了以下六种可用于癌症诊断和/或治疗的肿瘤特异性抗原。1)磷脂酰肌醇蛋白聚糖-3（GPC 3）; GPC 3是一种癌胚抗原和GPI锚定的膜蛋白。GPC 3在肝细胞癌（HCC）和黑色素瘤中强表达，但在各种正常成人组织中不表达。在约40%的HCC和黑素瘤患者中检测到血清可溶性GPC 3。值得注意的是，这些癌症的早期患者血清GPC 3呈阳性。GPC 3肽在体外刺激人外周血单个核细胞（PBMC）或刺激人外周血单个核细胞（PBMC）产生GPC 3肽特异性和MHC I类限制性CTL。 ...更多信息 小鼠的体内培养。用GPC 3肽脉冲的骨髓来源的树突状细胞（DC）预免疫的小鼠以CD 8 ^+ CTL依赖的方式保护移植的结肠癌细胞系C26的生长，C26转染小鼠GPC 3。2)增殖潜能相关蛋白（PP-RP）是一种在有丝分裂过程中与染色体共定位的核蛋白。PP-RP在食管癌细胞中呈强表达，在睾丸和胎盘中呈中等表达，而在许多正常组织中不表达。RNA干扰抑制PP-RP基因表达可抑制食管癌细胞增殖，PP-RP高表达与患者预后不良相关。PP-RP衍生肽刺激PBMC可产生人CTL，这些CTL在体外和移植人癌细胞的裸鼠体内均能杀伤食管癌细胞系。3)KM-HN-1、HSP-105、CLP和KM-PA 2;这些抗原使用癌症患者血清和从癌细胞或睾丸建立的cDNA表达文库通过SEREX方法鉴定。这些抗原在几种类型的癌细胞和几种正常组织中以较低水平强烈表达。产生了对源自这些抗原的肽特异性的CTL，它们杀死了人和小鼠中的癌细胞。4)胚胎干（ES）细胞衍生的DC疫苗;我们成功地增强抗肿瘤免疫的小鼠免疫与ES细胞衍生的DC同时表达基因编码的抗原和趋化因子。少

项目成果

Identification of a novel human cancer/testis antigen, KM-HN-1, recognized by cellular and humoral immune responses

• DOI: 10.1158/1078-0432.ccr-04-0475
• 发表时间: 2004-09-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Monji, M;Nakatsura, T;Nishimura, Y
• 通讯作者: Nishimura, Y

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伊藤博：“HLA II 类分子的抗原呈递和疾病易感性”分子医学专题“基因组多样性和功能分析 - MHC 多态性和疾病易感性”37・5。

Minohara, M.: "Differences between T cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls"Tissue Antigens. 57. 447-456 (2001)

Minohara, M.：“视脊髓和传统形式的多发性硬化症和健康对照中 T 细胞对主要髓磷脂蛋白衍生肽的反应性之间的差异”组织抗原。

Nishimura, Y.: "(review) Molecular and cellular analyses of HLA class II -associated susceptibility to autoimmune diseases in the Japanese population"Modern Rheumatology. 11. 103-112 (2001)

Nishimura, Y.：“（评论）日本人群中 HLA II 类相关的自身免疫性疾病易感性的分子和细胞分析”现代风湿病学。

中面哲也, 西村泰治: "CDNAマイクロアレイ解析による腫瘍特異抗原の探索"臨床免疫. 印刷中. (2004)

Tetsuya Nakamen、Yasuharu Nishimura：“通过 cDNA 微阵列分析寻找肿瘤特异性抗原”临床免疫学 (2004)。