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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591326/
• 关键词: メラノーマ; 免疫抑制; 養子細胞移入療法; 未熟骨髄由来細胞; ケモカイン

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.

与黑色素瘤一样，与许多其他恶性肿瘤一样，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。髓样衍生的抑制细胞（MDSC）在实验模型和患者中导致肿瘤引起的免疫功能障碍。虽然CD11b^+ Gr1^+髓样细胞是小鼠MDSC的众所周知的标记，但仅报道了有限数量的文献，用于急剧动员含B16黑色素瘤的C57BL/6小鼠CD11B^+ GR1^+ MDSC。为了寻找C57BL/6小鼠中CD11B^+ GR1^+ MDSC的动员条件，使用一些免疫缺陷的小鼠研究了CD11b^+ Gr1^+细胞的种群大小。通过流式细胞仪分析评估了B16含有黑色素瘤和无黑色素瘤小鼠的CD11B^+ GR1^+细胞的动员。此外，还使用形成白介素（IL）-4表达B16黑色素瘤肿瘤的小鼠来评估CD11b^+ Gr1^+细胞动员的成就。 C57BL/6野生型小鼠中的B16黑色素瘤较少动员CD11b^+ Gr1^+髓样细胞，但是CD11B^+ GR1^+细胞在RAG1 - / - / - 和TBX - / - 小鼠中显着动员，这些小鼠缺乏T和B细胞以及Th1-th1-type免疫反应。此外，表达IL-4的B16黑色素瘤小鼠促进了与F4/80^+巨噬细胞减少的免疫缺陷小鼠中CD11B^+ GR1^+ MDSC的动员。此外，我们发现C-X-C型趋化因子CXCL17（DMC/VCC-1）的最新成员募集了未成熟的髓样细胞并增强早期肿瘤进展。我们的数据表明，CXCL17在肿瘤细胞中的异常表达募集了未成熟的髓样细胞，并通过血管生成促进早期肿瘤进展。

项目成果

光イメージングが開く新しいトランスレーショナル研究.ツール.教育講演

光学成像开辟新的转化研究、工具、教育讲座

• 发表时间: 2009
• 作者: Miyagaki T;Sugaya M;Kadono T;Murakami T;Okochi H;Tamaki K;Sato S.;村上孝;Murakami T;村上孝
• 通讯作者: 村上孝

Transcriptional modulation using histone deacetylase inhibitors for cancer immunotherapy in "Experimental and Applied Immunotherapy"

“实验与应用免疫疗法”中使用组蛋白脱乙酰酶抑制剂进行转录调节用于癌症免疫疗法

• 发表时间: 2010
• 作者: Sato A;Murakami T;et al.;村上孝;Murakami T
• 通讯作者: Murakami T

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。

• 发表时间: 2009
• 期刊: Clin Cancer Res 5(9)
• 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.

Adenosine generation by CD39/ENTPD1 on CD4^+Foxp3^+ regulatory T cells dampens anti-tumor immunity.

CD4^ Foxp3^ 调节性 T 细胞上的 CD39/ENTPD1 产生腺苷会抑制抗肿瘤免疫。

• 发表时间: 2010
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Sun X;Wu Y;Gao W;Enjyoji K;Csizmadia E;Muller CE;Murakami T;et al.
• 通讯作者: et al.

Bio-luminescent imaging of the brain metastasis in a xenogeneic tumor transplantation mouse model.

异种肿瘤移植小鼠模型脑转移的生物发光成像。

• 发表时间: 2009
• 作者: Chun AL N;Matsui A;Murakami T
• 通讯作者: Murakami T