Regulation of Tumor Associated Macrophages by TGF-beta

TGF-β 对肿瘤相关巨噬细胞的调节

• 批准号: 8050532
• 负责人: Venkateshwar G Keshamouni
• 金额: $ 27.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-05 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050532
• 关键词: Adaptor Signaling Protein; Antigen Receptors; Bone Marrow Transplantation; Cancer Biology; Cell Line; Cell Proliferation; Cells; Coculture Techniques; Cytokine Receptors; Data; Dose; Effector Cell; Evolution; Family; Family member; Heat shock proteins; Human; Hyaluronic Acid; IRAK1 gene; IRAK3 gene; Immune; Immune Cell Activation; Immune Tolerance; Immune response; Immune system; Immunosuppressive Agents; Implant; Inflammation; Interferons; Interleukin-12; Lewis Lung Carcinoma; Lung Neoplasms; Lymphocyte; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myelogenous; Necrosis; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patients; Pattern; Peritoneal Macrophages; Phenotype; Phosphotransferases; Plasma; Play; Population; Process; Production; Protein-Serine-Threonine Kinases; Receptor Signaling; Recruitment Activity; Regulation; Role; Signal Transduction; Staging; TNF gene; TRAF6 gene; Time; Toll-like receptors; Transforming Growth Factor beta; Tumor Antigens; Tumor Promoters; Tumor Suppressor Proteins; Tumor-Derived; Wild Type Mouse; angiogenesis; base; cancer cell; carcinogenesis; cytokine; cytotoxic; cytotoxicity; ds-DNA; human IRAK1 protein; human TLR8 protein; implantation; in vivo; insight; macrophage; monocyte; neoplastic cell; outcome forecast; pathogen; protein protein interaction; receptor; receptor binding; response; subcutaneous; therapeutic target; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Tumor associated macrophages (TAM) constitute one of the major components of the immune cell infiltrate observed in the tumor microenvironment (TME) of virtually all types of malignancies. Emerging data implicates macrophages as key regulators of tumor cell proliferation, angiogenesis metastasis and survival. Many factors present within the TME including TGF-¿, allow tumors to routinely circumvent host mediated immune responses and redirect TAM activities for successful tumor progression. However, the molecular mechanism(s) underlying such a process are not known. In early stages of carcinogenesis TGF-¿ acts as tumor suppressor and in late stages as tumor promoter. Consistent with the tumor promoting function, TGF-¿ is known to have a broader influence on the immune system partly through cross-talk between TGF-¿ signaling intermediates and the components of both cytokine and antigen receptors including Toll-like receptors. The family of Toll-Like Receptors (TLRs) is an important mediator of the innate immune responses by immune cells and activation of these receptors trigger the production of several molecules involved in antitumoral responses including IFNs. In TME, what exactly triggers TLR signaling in macrophages is not known. However, The TME is rich in host derived molecules, including heat shock proteins, double stranded DNA from necrotic tumor cells and Hyaluronic acid that can potentially activate macrophage TLR signaling to trigger anti-tumoral responses. IRAK-M is an inactive ser/thr kinase, potent negative regulator of TLR signaling and predominantly expressed in macrophages. Our studies show that when co-cultured, human lung cancer cells induce IRAK-M expression in human monocytes/macrophages. TGF-¿ induces IRAK-M expression in human monocytes/macrophages in time and dose dependent manner. In-vivo studies in IRAK-M-/- mice showed a significant inhibition in tumor growth of subcutaneously implanted syngeneic Lewis-lung carcinoma cells. Analysis of TAMs purified from wild type mice demonstrated enhanced IRAK-M expression compared to peritoneal macrophages from same mice. TAMs from IRAK-M-/- mice demonstrated enhanced expression of proinflammatory and anti-tumor cytokines. Hypothesis: Based on above observations, we propose that tumor cell production of TGF-¿ results in IRAK-M expression by TAMs which functions to antagonize TLR signaling. This allows tumors to circumvent potential TLR mediated anti-tumor responses of macrophages and contribute to acquisition of distinct TAM phenotype. Conversely, disruption of IRAK-M expression may promote anti-tumor responses in TAMs and inhibit tumor growth and metastasis. Specific aims: 1) to determine the role of IRAK-M in lung tumor growth and metastasis using syngeneic heterotopic and orthotopic models of lewis lung carcinoma in IRAK-M-/- mice. 2) to determine the contribution of IRAK-M to the immunosuppressive phenotype of TAMs. 3) to determine whether the primary effector cell critical for tumor growth inhibition in IRAK-M-/- mice is of myeloid origin, by bone marrow transplantation 4) determine the mechanism of TGF-¿-induced IRAK-M expression in macrophages.

描述（由申请方提供）：肿瘤相关巨噬细胞（TAM）是几乎所有类型恶性肿瘤的肿瘤微环境（TME）中观察到的免疫细胞浸润的主要成分之一。新出现的数据表明巨噬细胞是肿瘤细胞增殖、血管生成、转移和存活的关键调节因子。TME中存在的许多因子，包括TGF-β，允许肿瘤常规地规避宿主介导的免疫应答并重新定向TAM活性以成功地进行肿瘤进展。然而，这种过程背后的分子机制尚不清楚。在癌变的早期阶段，TGF-β作为肿瘤抑制因子，在晚期阶段作为肿瘤促进因子。与肿瘤促进功能一致，已知TGF-β对免疫系统具有更广泛的影响，部分通过TGF-β信号传导中间体与细胞因子和抗原受体（包括Toll样受体）的组分之间的串扰。Toll样受体（TLR）家族是免疫细胞先天免疫反应的重要介体，这些受体的激活会触发参与抗肿瘤反应的几种分子（包括IFN）的产生。在TME中，究竟是什么触发了巨噬细胞中的TLR信号传导尚不清楚。然而，TME富含宿主衍生的分子，包括热休克蛋白、来自坏死肿瘤细胞的双链DNA和透明质酸，其可以潜在地激活巨噬细胞TLR信号传导以触发抗肿瘤反应。IRAK-M是一种失活的ser/thr激酶，是TLR信号传导的有效负调节剂，主要在巨噬细胞中表达。我们的研究表明，当共培养时，人肺癌细胞诱导人单核细胞/巨噬细胞中的IRAK-M表达。TGF-β以时间和剂量依赖性方式诱导人单核细胞/巨噬细胞中的IRAK-M表达。在IRAK-M-/-小鼠中的体内研究显示，皮下植入的同基因Lewis肺癌细胞的肿瘤生长受到显著抑制。从野生型小鼠纯化的TAM的分析表明，与来自相同小鼠的腹膜巨噬细胞相比，IRAK-M表达增强。来自IRAK-M-/-小鼠的TAM表现出促炎和抗肿瘤细胞因子的表达增强。假设：基于上述观察，我们提出肿瘤细胞产生TGF-β导致TAM表达IRAK-M，其功能是拮抗TLR信号传导。这允许肿瘤规避巨噬细胞的潜在TLR介导的抗肿瘤应答，并有助于获得不同的TAM表型。相反，IRAK-M表达的破坏可促进TAM中的抗肿瘤应答并抑制肿瘤生长和转移。具体目标：1）使用IRAK-M-/-小鼠中的刘易斯肺癌的同基因异位和原位模型来确定IRAK-M在肺肿瘤生长和转移中的作用。2)以确定IRAK-M对TAM的免疫抑制表型的贡献。3)通过骨髓移植确定IRAK-M-/-小鼠中对肿瘤生长抑制至关重要的主要效应细胞是否为髓系来源4）确定TGF-β诱导的巨噬细胞中IRAK-M表达的机制。