Ontogeny and Function of Tumor-associated Macrophages

 描述（由申请人提供）：肿瘤微环境由多种基质细胞类型组成，其不同功能促进恶性肿瘤。肿瘤相关的骨髓细胞，包括巨噬细胞，已经涉及促进肿瘤生长和肿瘤免疫逃避，并且与癌症患者的不良预后相关。然而，这些细胞所采用的分化途径及其免疫抑制机制在很大程度上是未知的。使用一个自体乳腺肿瘤模型，我们最近发现，肿瘤生长诱导分化的一个独特的子集的肿瘤相关的巨噬细胞（TAM）的炎症单核细胞。基因表达谱研究表明，与乳腺组织巨噬细胞（MTM）相比，TAM获得Notch依赖的基因表达特征。Notch途径的关键转录调节因子RBPJ的基因消融导致TAM的选择性损失和低肿瘤负荷，同时恢复肿瘤浸润性细胞毒性T细胞应答。在本申请中，我们将使用功能丧失和获得小鼠模型来确定参与TAM分化的确切Notch受体和Notch配体，并探索Notch的组成型活性形式的表达是否激活非荷瘤小鼠中的TAM分化程序。此外，TAMs中精确的Notch依赖性基因表达程序将被阐明。与MTM相比，TAM表达高水平的α v β 8整联蛋白。在自身免疫性疾病模型中，由骨髓细胞表达的α v β 8整联蛋白对于通过免疫抑制细胞因子TGF-β 1的活化诱导T细胞耐受是必需的。使用T细胞培养系统，我们将研究TAM是否作为抗原呈递细胞发挥功能，并通过参与TGF-β通路来抑制T细胞应答。此外，TAM表达的β 8整联蛋白在控制T细胞对肿瘤耐受性中的决定性功能将用骨髓细胞特异性Itgb 8缺陷小鼠品系测定.这些研究的完成不仅将阐明肿瘤引起的炎症反应的性质，而且还将为人类乳腺癌和其他上皮细胞来源的癌症的治疗干预提供见解。

 DESCRIPTION (provided by applicant): The tumor microenvironment consists of numerous stromal cell types whose diverse functions foster malignancy. Tumor-associated myeloid cells, including macrophages, have been implicated in promoting tumor growth and tumor immune evasion, and are associated with poor prognosis in cancer patients. However, the differentiation pathway employed by these cells and their mechanisms of immune suppression are largely uncharacterized. Using an autochthonous mammary tumor model, we have recently found that tumor growth induces the differentiation of a unique subset of tumor-associated macrophages (TAMs) from inflammatory monocytes. Gene expression profiling studies reveal that compared to mammary tissue macrophages (MTMs), TAMs acquire a Notch-dependent gene expression signature. Genetic ablation of the key transcriptional regulator of the Notch pathway, RBPJ, results in a selective loss of TAMs and low tumor burden concomitant with the restoration of tumor-infiltrating cytotoxic T cell responses. In this application, we will use loss- and gain-of-function mouse models to determine the exact Notch receptor(s) and Notch ligand(s) involved in TAM differentiation, and to explore whether the expression of a constitutively active form of Notch activates the TAM differentiation program in non-tumor bearing mice. Furthermore, the precise Notch- dependent gene expression program in TAMs will be elucidated. Compared to MTMs, TAMs express high levels of the avß8 integrin. In autoimmune disease models, the avß8 integrin expressed by myeloid cells is essential for the induction of T cell tolerance via the activation of the immunosuppressive cytokine TGF-ß1. Using a T cell culture system, we will investigate whether TAMs function as antigen-presenting cells, and suppress T cell responses by engaging the TGF-ß pathway. In addition, the definitive function of TAM- expressed ß8 integrin in the control of T cell tolerance to tumors will be determined with a strain of myeloid cell- specific Itgb8-deficient mice. Completion of these studies will not only illuminate the natur of tumor-elicited inflammatory responses but also provide insights into the therapeutic intervention in human breast cancer and perhaps other cancers of epithelial cell origin.