The study of immunosuppressive mechanisms induced by gastrointestinal cancer during epithelial-mesnchymal transition and clinical application of this target therapy

胃肠癌上皮间质转化过程中免疫抑制机制的研究及靶向治疗的临床应用

• 批准号: 18591484
• 负责人: SAKURAI Toshiharu
• 金额: $ 2.57万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591484/
• 关键词: epithelial-mesenchymal transition; gastroenterogic cancer; Snail; immunosuppression; ラマン分光; 子宮頸癌; 細胞診; コルポスコピー; 免疫応答

Epithelial-mesenchymal transition (EMT) is thought to be a key step toward metastases, and the molecular mechanisms have been investigated from aspects of cancer cells. However the interaction between host immunity and the tumor cells during EMT has not been clarified yet In this study, we first established human pancreatic cancer cell line Panc-1 cells with typical EMT features such as decreased adhesion and increased invasion by transduction with snail gene, which is one of the essential transcription factor governing EMT. lb analyze how the snail transfectants would affect immune responses, we then cultured human PBMCs with the snail transfectants. In the culture with snail transfectants, immunosuppressive cells such as impaired CD11c^+ cells and CD4^+FoxP3^+ cells were increased as compared with the culture with the mock transfectant We further conducted GeneChip array analysis to compare gene expression between the snail transfectant and the parental cells, and identified the specific mediators involved in the snail-induced immunosuppressive mechanisms. The mAbs specific for the molecules significantly inhibited both induction of immunosuppression and tumor invasion. These data demonstrate that snail^+ tumor cells during EMT simultaneously induce immunosuppressive microenvironment, leading to acceleration of tumor metastasis. Blockade of the EMT-related molecules would be effective in simultaneously suppressing tumor metastasis and immunosuppression, both which are still critical issues in cancer therapy. This strategy could be promising to improve anti-tumor efficacies induced by various therapies for patients with cancers.

上皮间质转化（EMT）被认为是肿瘤转移的关键步骤，其分子机制已从肿瘤细胞的角度进行了研究。然而，EMT过程中宿主免疫和肿瘤细胞之间的相互作用尚未阐明。本研究首先通过转导调控EMT的关键转录因子snail基因，建立了具有EMT典型特征的人胰腺癌细胞株Panc-1。为了分析snail转染子如何影响免疫应答，我们然后用snail转染子培养人PBMC。在用snail转染子培养的细胞中，免疫抑制细胞如受损的CD 11 c ^+细胞和CD 4 ^+ FoxP 3 ^+细胞比用mock转染子培养的细胞增加。我们进一步进行了基因芯片阵列分析，以比较snail转染子和亲本细胞之间的基因表达，并鉴定了参与snail诱导的免疫抑制机制的特异性介质。特异性单克隆抗体的分子显着抑制免疫抑制和肿瘤侵袭的诱导。这些数据表明，EMT期间的snail^+肿瘤细胞同时诱导免疫抑制微环境，导致肿瘤转移加速。阻断EMT相关分子将有效地同时抑制肿瘤转移和免疫抑制，这两者仍然是癌症治疗中的关键问题。这种策略可能有希望提高癌症患者各种疗法诱导的抗肿瘤疗效。

项目成果

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

Molecular mechanisms for generation of immunosuppressive microenvironment by cancer cells

癌细胞产生免疫抑制微环境的分子机制

• 发表时间: 2007
• 作者: Yutaka Kawakami;Hidetoshi Sumimoto;Chie Kudo;Tomonori Yaguchi
• 通讯作者: Tomonori Yaguchi

Dendritic cell based personalized immunotherapy based on cancer antigen research

基于癌抗原研究的树突状细胞个性化免疫治疗

• 发表时间: 2008
• 期刊: Frontiers in Bioscience 1;13
• 作者: Kawakami Y;Fujita T;Kudo C;Sakurai T;Udagawa M;Yaguchi T;Hasegawa G;Hayashi E;Ueda Y;Iwata T;Wang Q;Okada S;Tsukamoto N;Matsuzaki Y;Sumimoto H.
• 通讯作者: Sumimoto H.