Molecular-based analysis of HLA class I processing machinery defects in human melanoma

人类黑色素瘤 HLA I 类加工机械缺陷的分子分析

基本信息

批准号：
16591106
负责人：
KAGESHITA Toshiro
金额：
$ 2.24万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591106/
关键词：
melanoma peptide antigens antigen processing machinery HLA class I ペプチド提

项目摘要

One of the large concerns in melanoma T cell based immunotherapy is the immune escape phenomenon resulting from loss of melanoma associated antigens and/or HLA class I. The head investigator has been analyzing the mechanisms of down regulation of HLA class I in melanocytic cells.In the present study, molecular-based analysis of HLA class I processing machinery defects in human melanoma was investigated using monoclonal antibodies to melanoma associated antigens (MART-1, gp100, tyrosinase), to molecules associated with antigen processing machinery (TAP-1, TAP-2, LMP-2, LMP-7, LMP-10, Z, Delta, Tapacin, Calnexin, Calreticulin), and to HLA class I (HLA class I-heavy chain, HLA class I-light chain). The head investigator already found the antigen-retrieval method for all these monoclonal antibodies in formalin-fixed, paraffin-embedded tissue sections.The head investigator found the following points :1)Melanoma associated antigens (MART-1, gp100, tyrosinase) were expressed highly in primary … More melanoma lesions. However, these expressions were down regulated in some metastatic melanoma lesions, especially in the lesions with low melanin content.2)Among the molecules associated with antigen processing machinery, delata and calreticulin were ubiquitously expressed in primary and metastatic lesions. Expression of TAP-1 and TAP-2 were remarkably down regulated especially in metastatic lesions.3)Expression of HLA class I heavy chain and light chain were remarkably down regulated in metastatic lesions.4)There was a close association between HLA class I and TAP-1/TAP-2 down regulation.5)There was an inverse association between CD8 infiltration and HLA class I down regulation.These data suggest that HLA class I expression is necessary for presenting melanoma associated antigens to CD8 T cells and TAP-1 and TAP-2 are most involved molecules in HLA class I down regulation. Also these data suggest that abnormality of these molecules are associated with immune escape mechanism in human melanoma. Less

基于黑色素瘤 T 细胞的免疫治疗中最令人担忧的问题之一是由于黑色素瘤相关抗原和/或 I 类 HLA 丢失而导致的免疫逃逸现象。首席研究员一直在分析黑色素细胞中 HLA I 类下调的机制。本研究使用黑色素瘤相关抗原（MART-1、gp100、酪氨酸酶）的单克隆抗体对人类黑色素瘤中 HLA I 类加工机制缺陷进行分子分析，与抗原加工机制相关的分子（TAP-1、TAP-2、LMP-2、LMP-7、LMP-10、Z、Delta、Tapacin、Calnexin、Calreticulin）以及 HLA I 类（HLA I 类重链）链，HLA I 类轻链）首席研究员已经在福尔马林固定、石蜡包埋的组织切片中找到了所有这些单克隆抗体的抗原修复方法。首席研究员发现以下几点：1）黑色素瘤相关抗原（MART-1、gp100、酪氨酸酶）在原发性黑色素瘤病灶中高表达，然而，这些表达在一些转移性黑色素瘤病灶中下调，尤其是在低表达的病灶中。 2）在与抗原加工机制相关的分子中，delata和calreticulin在原发性和转移性病变中普遍表达。 TAP-2 罕见下调，尤其是在转移性病灶中。3）HLA I 类重链和轻链的表达在转移性病灶中罕见下调。4）HLA I 类与 TAP-1/TAP- 之间存在密切相关性。 2 下调。5) CD8 浸润与 HLA I 类下调之间存在负相关。这些数据表明 HLA I 类表达对于将黑色素瘤相关抗原呈递给 CD8 T 细胞和 TAP-1 和TAP-2 是 HLA I 类下调中最重要的分子，这些数据还表明这些分子的异常与人类黑色素瘤的免疫逃逸机制有关。

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical significance of MHC class II-associated invariant chain expression in human gastric carcinoma.

人胃癌中 MHC II 类相关不变链表达的临床意义。

DOI：
发表时间：
2005
期刊：
Oncology Reports 14
影响因子：
0
作者：
Kaoru Ohtaki;Michiko Aihara;Hinako Takahashi;Hiroyuki Fujita;Kazuo Takahashi;Toshiya Funabashi;Tsutomu Hirasawa;Zenro Ikezawa;Kageshita T
通讯作者：
Kageshita T

エビデンスに基づいた癌化学療法ハンドブック

循证癌症化疗手册

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Hayashi Hidetoshi;Chiba Yasutaka;Sakai Kazuko;Fujita Tomonobu;Yoshioka Hiroshige;Sakai Daisuke;Kitagawa Chiyoe;Naito Tateaki;Takeda Koji;Okamoto Isamu;Mitsudomi Tetsuya;Kawakami Yutaka;Nishio Kazuto;Nakamura Shinichiro;Yamamoto Nobuyuki;Nakagawa Kazuhiko;Nokihara H;Naito T;Naito T;Sato K;Tanaka A;Hayata A;Kikuchi T;Schuler M;Sekine I;Azuma K;Nosaki K;Goto K;Yoh K;Atagi S;Hiroaki Akamatsu;Makoto Nishio;James Yang;Takehito Shukuya;Murakami Hiroyasu;Akamatsu H;Kambayashi S;Koh Y;Shibaki R;Otsubo K;Takiguchi Y;Yamamoto N;Yamamoto N;Sato K;Shibaki R;Akamatsu H;Oyanagi J;Koh Y,;Hayakawa K;Kim Y;Koh Y;Akamatsu H;Kim W;Yagi S;Hiroaki Akamatsu;Yasuhiro Koh;Hiroaki Akamatsu;山本信之;山本信之
通讯作者：
山本信之

Histopathologic characteristics of malignant melanoma affecting mucous membranes : A unifying concept of histogenesis.

影响粘膜的恶性黑色素瘤的组织病理学特征：组织发生的统一概念。

DOI：
发表时间：
2004
期刊：
Pathology. 36
影响因子：
0
作者：
Saida T;Kawachi S;Takata M;Kurita H;Kurashina K;Kageshita T;Tonogi M;Okazaki Y;Yamane G;Takubo K;Ueyama Y.
通讯作者：
Ueyama Y.

Comparison of dermoscopic and histopathologic findings in a mucous melanoma of the lip.

唇部粘液黑色素瘤的皮肤镜和组织病理学结果的比较。

DOI：
发表时间：
2005
期刊：
Brit. J. Dermatol 152
影响因子：
0
作者：
Fujii K;Tsuii K;Matsuura H;Okazaki;Takahashi S;Arata J;Iwatsuki K;Hajimu OURA;Kageshita T
通讯作者：
Kageshita T

Human high molecular weight-melanoma associated antigen : structural features functional role in the biology of melanoma cells and clinical significance.

人类高分子量黑色素瘤相关抗原：结构特征在黑色素瘤细胞生物学中的功能作用和临床意义。