Immune response and escape in human cancers

人类癌症的免疫反应和逃逸

• 批准号: 16209013
• 负责人: SATO Noriyuki
• 金额: $ 29.79万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209013/
• 关键词: cancer vaccine; survivin; SYT-SSX; HLA class I down regulation; immune escape; epigenetics; HAD inhibitor; HSP90; エスケープ; ヒト癌免疫治療; HLAクラス1; HDAC; 抗原ペプチド; 腫瘍抗原; β2ミクログロブリン; 免疫治療; mAb; 癌抗原ペプチドワクチン; MHC I; II; CIITA; 病理標本

The investigation of human tumor immunotherapy has remarkably advanced in the past decade. In our laboratory, human tumor antigens and their HLA-A24-restricted immunogenic peptide epitopes were determined to develop therapeutic and prophylactic human cancer vaccines. Among these peptides, survivin 2B peptide derived from survivin, an inhibitor of apoptosis protein (IAP), is immunogenic in more than 50 % of cancer patients with a wide variety of tumors, including colon, pancreas, lung, breast, urinary bladder and oral cancers. It is now under clinical and with careful immunological monitoring we will finally be able to know if these vaccines can work clinically.To develop a potent clinical therapeutic protocol, the immunological tumor escape mechanism should be more thoroughly examined in human tumor materials. To this end, anti-HLA-A, B, and C allele-specific monoclonal antibody EMR8-5, which can be used in routine paraffin-embedded sections, was successfully established. Unexpectedly, our data indicated that a high percentage of human cancers, particularly breast and prostate cancers, lost HLA-class I molecules in their primary cancer tissues. We will discuss possibilities for resolution of this important old but yet new problem.Although recent evidence has been accumulating for an important role of the heat shock proteins (HSPs) as so-called danger signals in initiating innate immunity and consequently activating acquired immunity, the precise immunological basis for this phenomenon remains to be elucidated. Our study indicated that certain HSP-chaperoned immunogenic peptides, particularly HSP90, could efficiently enter the cross-priming pathway in dendritic cells. Interestingly, this cross-priming was TAP-independent and followed endocytic pathways. We also showed that HSP90-chaperoned peptide complexes could work as a potential tumor therapeutic vaccine in the HLA-A24 transgenic mouse model.

过去十年，人类肿瘤免疫疗法的研究取得了显着进展。在我们的实验室中，确定了人类肿瘤抗原及其 HLA-A24 限制性免疫原性肽表位，以开发治疗性和预防性人类癌症疫苗。在这些肽中，生存素 2B 肽源自生存素，一种凋亡蛋白 (IAP) 抑制剂，对超过 50% 的患有多种肿瘤的癌症患者具有免疫原性，包括结肠癌、胰腺癌、肺癌、乳腺癌、膀胱癌和口腔癌。癌症。现在正处于临床阶段，通过仔细的免疫学监测，我们最终将能够知道这些疫苗是否可以在临床上发挥作用。为了开发有效的临床治疗方案，应该在人类肿瘤材料中更彻底地检查免疫学肿瘤逃逸机制。为此，成功建立了可用于常规石蜡包埋切片的抗HLA-A、B、C等位基因特异性单克隆抗体EMR8-5。出乎意料的是，我们的数据表明，很高比例的人类癌症，特别是乳腺癌和前列腺癌，在其原发癌组织中丢失了 HLA-I 类分子。我们将讨论解决这个重要的老问题但又是新问题的可能性。尽管最近越来越多的证据表明热休克蛋白（HSP）作为所谓的危险信号在启动先天免疫并随后激活获得性免疫方面发挥着重要作用，但这种现象的精确免疫学基础仍有待阐明。我们的研究表明，某些 HSP 陪伴的免疫原性肽，特别是 HSP90，可以有效地进入树突状细胞中的交叉引发途径。有趣的是，这种交叉启动不依赖于 TAP，并且遵循内吞途径。我们还表明，HSP90 陪伴的肽复合物可以作为 HLA-A24 转基因小鼠模型中潜在的肿瘤治疗疫苗。

项目成果

サバイビン由来HLA-A24結合性癌抗原ペプチド

生存素衍生的 HLA-A24 结合癌抗原肽

• 发表时间: 2004

Inhibition of endogenous MHC class II-restricted antigen presentation by tacrolimus (FK506) via FKBP51

• DOI: 10.1002/eji.200636392
• 发表时间: 2007-07-01
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Imai, Akihito;Sahara, Hiroeki;Sato, Noriyuki
• 通讯作者: Sato, Noriyuki

A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptotis proteins.

一种有效的免疫原性通用癌症疫苗，针对存活蛋白（一种凋亡蛋白抑制剂）。

• 发表时间: 2005
• 期刊: Clin.Cancer Res. 11
• 作者: Idenoue;S.
• 通讯作者: S.

Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway

• DOI: 10.4049/jimmunol.179.3.1803
• 发表时间: 2007-08-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Kurotaki, Takehiro;Tamura, Yasuaki;Sato, Noriyuki
• 通讯作者: Sato, Noriyuki

A quest for therapeutic antigens in bone and soft tissue sarcoma.

• DOI: 10.1186/1479-5876-3-31
• 发表时间: 2005-08-08
• 期刊: JOURNAL OF TRANSLATIONAL MEDICINE
• 影响因子: 7.4
• 作者: Kawaguchi, S;Wada, T;Tsukahara, T;Ida, K;Torigoe, T;Sato, N;Yamashita, T
• 通讯作者: Yamashita, T