Ontogeny and Function of Tumor-associated Macrophages

 描述(申请人提供)：肿瘤微环境由多种不同功能的间质细胞类型组成，它们促进了恶性肿瘤的发生。肿瘤相关髓系细胞，包括巨噬细胞，参与促进肿瘤生长和肿瘤免疫逃逸，并与癌症患者预后不良有关。然而，这些细胞的分化途径及其免疫抑制机制在很大程度上尚不清楚。利用自体乳腺肿瘤模型，我们最近发现，肿瘤生长诱导了肿瘤相关巨噬细胞(TAMs)从炎性单核细胞分化为一个独特的亚群。基因表达谱研究表明，与乳腺组织巨噬细胞(MTM)相比，TAM获得了Notch依赖的基因表达特征。基因消融Notch途径的关键转录调节因子RBPJ，导致TAMs的选择性丢失和低肿瘤负担，同时恢复肿瘤浸润性细胞毒性T细胞反应。在这项应用中，我们将使用功能丧失和功能获得的小鼠模型来确定参与分化的确切的Notch受体(S)和Notch配体(S)，并探索在非荷瘤小鼠中Notch的表达是否激活了的分化程序。此外，还将阐明TAMS中精确的Notch依赖的基因表达程序。与MTM相比，TAMS表达高水平的av？8整合素。在自身免疫性疾病模型中，髓系细胞表达的av？8整合素是通过激活免疫抑制细胞因子转化生长因子β1诱导T细胞耐受所必需的。利用T细胞培养系统，我们将研究TAMS是否作为抗原提呈细胞发挥作用，并通过参与转化生长因子β途径抑制T细胞反应。此外，表达的B-8整合素在控制T细胞对肿瘤的耐受性中的决定性作用将通过一种髓系细胞特异性Itgb8缺陷小鼠来确定。这些研究的完成不仅将阐明肿瘤引起的炎症反应的本质，还将为人类乳腺癌以及其他上皮细胞起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.