To clarify mechanism by which long-term antitumor immunity induced by GM-CSF gene transduced tumor cells is generated in the absence of LTB4/BLT1 signaling.

阐明在缺乏 LTB4/BLT1 信号传导的情况下，GM-CSF 基因转导的肿瘤细胞诱导产生长期抗肿瘤免疫的机制。

• 批准号: 21790387
• 负责人: INOUE Hiroyuki
• 金额: $ 2.66万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790387/
• 关键词: 腫瘍免疫; メモリーT細胞; BLT1; LTB4; GM-CSF; GVAX

In this study, we successfully identified CD4+T cells as a pivotal determinant responsible for developing long-term antitumor effect during re-rejection of rechallenge of WEHI3B cells, a mouse monocytic leukemia cell line, after observation of marked rejection of in vivo s.c. administration of GM-CSF gene transduced WEHI3B (WGM) cells. In addition, ratios of various memory CD4+T cells including stem central memory CD4+T and CD8+ T cells in lymph nodes (LNs) collected at day 46 were increased in BLT1 mice inoculated with WGM cells. As a prospective mechanism, our immunological findings suggest that absence of LTB4/BLT1 signaling facilitates effective and sustained generation of potent tumor associated antigens (TAAs) specific memory CD4+T cells by promoting activation of mature DCs in LNs and migration of TAAs phagocytosed DCs into LNs, subsequently leading to augmented adaptive immunities (Th1 and Th2 cells) and repressing a wide range of regulatory CD4+ T cells known to hinder antitumor immunity.

在这项研究中，我们通过观察小鼠单核白血病细胞系WEHI3B (GM-CSF基因转导的WEHI3B （WGM）细胞在体内的明显排斥反应，成功地发现CD4+T细胞是在对WEHI3B细胞再攻击的再排斥反应中发挥长期抗肿瘤作用的关键决定因素。此外，接种WGM细胞的BLT1小鼠在第46天收集的淋巴结（LNs）中各种记忆CD4+T细胞（包括干细胞中枢记忆CD4+T和CD8+ T细胞）的比例增加。作为一种前瞻性机制，我们的免疫学研究结果表明，LTB4/BLT1信号的缺失促进了有效和持续地产生有效的肿瘤相关抗原（TAAs）特异性记忆CD4+T细胞，通过促进LNs中成熟dc的激活和TAAs吞噬dc向LNs的迁移，随后导致适应性免疫（Th1和Th2细胞）的增强，并抑制了广泛的已知阻碍抗肿瘤免疫的调节性CD4+T细胞。

项目成果

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Blocking of the LTB4 Signaling Maintains the in vivo Antitumor Effects of GM-CSF in the tumor challenged BLT1-/- mice

阻断 LTB4 信号传导可维持 GM-CSF 在肿瘤攻击的 BLT1-/- 小鼠中的体内抗肿瘤作用

• 发表时间: 2008
• 作者: Haruka Nabeta;Hiroyuki Inoue;Mutsunori Iga;Yosuke Yokota;Ryo Kurita;Fumiyuki Sasaki;Koichi Takayama;Yoichi Nakanishi;Takehiko Yokomizo;Kenzaburo Tani.
• 通讯作者: Kenzaburo Tani.

Loss of LTB4 Signaling Confers the Long-Term Antileukemia Effects Induced by GM-CSF -Transduced Tumor in BLT1 deficient Mice

LTB4 信号传导的丧失赋予 BLT1 缺陷小鼠中 GM-CSF 转导肿瘤诱导的长期抗白血病作用

• 发表时间: 2008
• 作者: Hiroyuki Inoue;Yosuke Yokota;Haruka Nabeta;Mutsunori Iga;Chika Sakamoto;Fumiyuki Sasaki;Yoichi Nakanishi;Takehiko Yokomizo;Kenzaburo Tani.
• 通讯作者: Kenzaburo Tani.

Blocking LTB4 Signaling Confers the Long-Term Antitumor Effects Induced by GM-CSF-Transduced Tumor in BLT1 Deficient Mice

阻断 LTB4 信号传导可赋予 BLT1 缺陷小鼠 GM-CSF 转导肿瘤诱导的长期抗肿瘤作用

• 发表时间: 2008
• 作者: Hiroyuki Inoue;Yosuke Yokota;Haruka Nabeta;Mutsunori Iga;Chika Sakamoto^1;Fumiyuki Sasaki;Yoichi Nakanishi;Takehiko Yokomizo;Kenzaburo Tani.
• 通讯作者: Kenzaburo Tani.

サイトカインと癌治療臨床検査 第54巻6号

细胞因子和癌症治疗临床测试第 54 卷第 6 期

• 发表时间: 2010
• 作者: 井上博之;谷憲三朗
• 通讯作者: 谷憲三朗