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.

在过去的十年里，人类肿瘤免疫治疗的研究取得了显著的进展。本实验室确定了人类肿瘤抗原及其人类白细胞抗原A24限制性免疫原肽表位，用于研制治疗性和预防性人类肿瘤疫苗。在这些多肽中，由Survivin衍生的Survivin 2B多肽是一种凋亡抑制蛋白(IAP)，在超过50%的癌症患者中具有免疫原性，这些肿瘤包括结肠癌、胰腺癌、肺癌、乳腺癌、膀胱癌和口腔癌。目前正处于临床阶段，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。为了开发出有效的临床治疗方案，应该在人类肿瘤材料中更彻底地研究免疫肿瘤逃逸机制。为此，成功制备了可用于常规石蜡包埋切片的抗人类白细胞抗原-A、B、C等位基因特异性单抗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HLAI类分子。我们将讨论解决这一古老而又新的重要问题的可能性。尽管最近的证据表明热休克蛋白(HSPs)作为所谓的危险信号在启动先天性免疫从而激活获得性免疫中起着重要作用，但这种现象的确切免疫学基础仍有待阐明。我们的研究表明，某些HSP伴随的免疫原肽，特别是HSP90，可以有效地进入树突状细胞的交叉激发途径。有趣的是，这种交叉启动是不依赖于TAP的，并遵循内吞途径。我们还表明，HSP90-伴侣多肽复合体可以作为一种潜在的肿瘤治疗性疫苗在人类白细胞抗原-A24转基因小鼠模型中发挥作用。

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

Effect of human leukocyte antigen class I expression of tumor cells on outcome of intravesical instillation of bacillus Calmette-Guerin immunotherapy for bladder cancer

• DOI: 10.1158/1078-0432.ccr-06-0595
• 发表时间: 2006-08-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Kitamura, Hiroshi;Torigoe, Toshihiko;Tsukamoto, Taiji
• 通讯作者: Tsukamoto, Taiji

Aberrant expression and potency as a cancer immunotherapy target of IAP family, Livin/ML-IAP in Lung Cancer

IAP 家族 Livin/ML-IAP 在肺癌中的异常表达和作为癌症免疫治疗靶标的效力

• 发表时间: 2005
• 期刊: Clin. Cancer Res. 11
• 作者: Harlu;H.;Hirohashi;Y.;Torigoe;T.;Tamura;Y.;Aketa;K.;Kitamura;H.;Idenoue;S.;Hariu;M.;Kamiguchi;K.;Mano;Y.;Kanaseki;T.;Tsukahara;T.;Shijubo;N.;Sato;N.
• 通讯作者: N.

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.