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Mobilization of myeloid-derived suppressor cells in the melanoma progression and the study of the effective adoptive immunotherapy

黑色素瘤进展中骨髓源性抑制细胞的动员及有效过继免疫治疗的研究

基本信息

批准号：
20591326
负责人：
MURAKAMI Takashi
金额：
$ 2.91万
依托单位：
Jichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

With melanoma, as with many other malignancies, the immune-suppressive tumor microenvironment is a hallmark of cancer and a major obstacle to immune therapy. Myeloid-derived suppressor cells (MDSCs) contribute to immune dysfunctions induced by tumors both in experimental models and patients. While CD11b^+Gr1^+ myeloid cells are well-known markers for MDSCs in mice, only a limited number of literatures have been reported for drastic mobilization of CD11b^+Gr1^+ MDSCs in B16 melanoma-bearing C57BL/6 mice. To seek out mobilizing conditions of CD11b^+Gr1^+ MDSCs in C57BL/6 mice, the population size of CD11b^+Gr1^+ cells was investigated using some immunodeficient mice. Mobilization of CD11b^+Gr1^+ cells of B16 melanoma-bearing and melanoma-free mice was assessed by flow cytometric analysis. Moreover, achievement in mobilization of CD11b^+Gr1^+ cells was also evaluated using mice that formed interleukin (IL)-4-expressing B16 melanoma tumor. B16 melanoma in C57BL/6 wild-type mice less mobilizes CD11b^+Gr1^+ myeloid cells, but CD11b^+Gr1^+ cells were significantly mobilized in Rag1-/- and Tbx-/- mice that lack T and B cells and Th1-type immune response, respectively. Furthermore, IL-4-expressing B16 melanoma-bearing mice facilitated mobilization of CD11b^+Gr1^+ MDSCs in those immunodeficient mice in concomitant with the decrease of F4/80^+ macrophages. Furthermore, we found that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1), recruited immature myeloid-derived cells and enhances early tumor progression. Our data suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes early tumor progression through angiogenesis.

与许多其他恶性肿瘤一样，黑色素瘤的免疫抑制性肿瘤微环境是癌症的标志，也是免疫治疗的主要障碍。骨髓源性抑制细胞（MDSC）有助于实验模型和患者中肿瘤诱导的免疫功能障碍。虽然CD11b ^+ Gr1 ^+骨髓细胞是小鼠MDSC的已知标志物，但只有有限数量的文献报道了携带B16黑色素瘤的C57 BL/6小鼠中CD11b ^+ Gr1 ^+ MDSC的剧烈动员。为探讨CD11b ^+ Gr1 ^+ MDSCs在C57 BL/6小鼠体内的动员条件，采用免疫缺陷小鼠，观察CD11b ^+ Gr1 ^+ MDSCs的数量。通过流式细胞术分析评估了荷B16黑色素瘤小鼠和无黑色素瘤小鼠的CD 11b ^+ Gr1 ^+细胞的动员。此外，还使用形成表达白细胞介素（IL）-4的B16黑色素瘤的小鼠评估了CD11b ^+ Gr1 ^+细胞的动员效果。C57 BL/6野生型小鼠中的B16黑色素瘤较少动员CD 11 B ^+ Gr1 ^+骨髓细胞，但CD 11 B ^+ Gr1 ^+细胞在分别缺乏T和B细胞以及Th1型免疫应答的Rag1-/-和Tbx-/-小鼠中显著动员。此外，表达IL-4的B16黑色素瘤小鼠促进了这些免疫缺陷小鼠中CD11b ^+ Gr1 ^+ MDSC的动员，同时伴有F4/80 ^+巨噬细胞的减少。此外，我们发现C-X-C型趋化因子的最新成员CXCL17（DMC/VCC-1）招募未成熟的骨髓源性细胞并促进早期肿瘤进展。我们的数据表明，CXCL17在肿瘤细胞中的异常表达招募未成熟的骨髓源性细胞，并通过血管生成促进早期肿瘤进展。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification and metastatic potential of tumor-initiating cells in malignant rhabdoid tumor of the kidney.

肾恶性横纹肌瘤肿瘤起始细胞的鉴定和转移潜力。

DOI：
发表时间：
2009
期刊：
Clin Cancer Res 5(9)
影响因子：
0
作者：
Yanagisawa S;Kadouchi I;Yokomori K;Hirose M;Hakozaki M;Hojo H;Maeda K;Kobayashi E;Murakami T.
通讯作者：
Murakami T.

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