Mechanisms Underlying Functional Programs of Tumor-Associated Macrophages

描述（由申请人提供）：尽管进行了手术和全身治疗，但许多乳腺癌患者因转移而复发。临床结果如此糟糕的一个原因与目前理解乳腺癌生物学的方法有关。目前的范式不成比例地集中在肿瘤发生的内在遗传和表观遗传变化。然而，已经清楚的是，肿瘤细胞与宿主的相互作用促进了恶性进展。广泛的研究表明，乳腺肿瘤微环境的主要细胞外在因素是巨噬细胞，称为肿瘤相关巨噬细胞（TAM）。尽管高TAM密度与较差的预后相关，但这并不表明TAM总是促肿瘤发生的。事实上，与TAM浸润很少的患者相比，具有高TAM密度的患者比例显示出显着的寿命。这种功能二分法引入了TAM可以重新分类为M1（肿瘤抑制）或M2（肿瘤促进）亚型的概念，这让人想起CD 4 + Th 1-Th 2范例。值得注意的是，目前对人TAM的鉴定是基于单个表型标志物CD 68的表达，这不足以区分功能多样性。因此，我们将测试新的假设，即TAM表型反映了M1到M2亚型的平衡，这是由IRF 8，一个关键的骨髓依赖性转录因子的表达决定的。与其他IRF成员不同，IRF 8参与骨髓生成的不同阶段，并且是细胞因子/趋化因子（例如，IL-12、IL-18、CCL 5）对于抗肿瘤免疫是必需的。在TAM生物学中探索IRF 8状态的其他理由是基于我们最近在髓源性抑制细胞（MDSC）生物学中的工作，这是一种新发现的肿瘤促进髓样细胞群。在这里，我们表明IRF 8表达显著抑制MDSC扩增，与IRF 8在骨髓生成中的作用模式一致。为了检验我们的中心假设，我们提出了三个目的：1）确定小鼠乳腺肿瘤模型中IRF 8表达和TAM表型之间的因果关系; 2）确定极化细胞因子信号如何阻碍或抑制IRF 8表达以影响TAM表型;和3）确定将人TAM分层为IRF 8hi和IRF 8lo表达亚型是否改善乳腺癌的预后意义。总而言之，我们认为将TAM分成反映不同IRF 8反应性的亚型不仅为其功能多样性提供了机制基础，而且还阐明了跟踪患者结局的新方法。

DESCRIPTION (provided by applicant): Despite surgery and systemic treatment, many breast cancer patients relapse due to metastasis. One reason for such poor clinical outcomes concerns current approaches to understanding breast cancer biology. Current paradigms are disproportionately focused on intrinsic genetic and epigenetic changes underlying tumorigenesis. However, it has become clear that tumor cell interactions with the host facilitate malignant progression. Extensive studies reveal that a dominant cell-extrinsic element of the breast tumor microenvironment is the macrophage, termed tumor-associated macrophage (TAM). Although high TAM densities have been associated with a poorer prognosis, this does not indicate that TAMs are always pro-tumorigenic. In fact, proportions of patients with high TAM densities exhibit significant longevity compared to those with little TAM infiltration. This functional dichotomy introduces the notion that TAMs can be reclassified into M1 (tumor-suppressing) or M2 (tumor-promoting) subtypes reminiscent of the CD4+ Th1-Th2 paradigm. It is noteworthy that current identification of human TAMs is based on the expression of a single phenotypic marker, CD68, which is inadequate to distinguish functional diversity. Thus, we will test the novel hypothesis that TAM phenotype reflects the balance of M1 to M2 subtypes, which is determined by expression of IRF8, a key myeloid-dependent transcription factor. IRF8, unlike other IRF members is involved in diverse stages of myelopoiesis and is indispensable for cytokines/chemokines (e.g., IL-12, IL-18, CCL5) essential for antitumor immunity. Additional rationale for exploring IRF8 status in TAM biology is based on our recent work in myeloid-derived suppressor cells (MDSC) biology, a newly identified tumor-promoting myeloid population. Here, we showed that IRF8 expression significantly inhibited MDSC expansion, consistent with the mode of action of IRF8 in myelopoiesis. To test our central hypothesis, we propose three aims: 1) to determine the causal link between IRF8 expression and TAM phenotype in mouse mammary tumor models; 2) to determine how polarizing cytokine signals impede or repress IRF8 expression to impact TAM phenotype; and 3) to determine whether stratification of human TAMs into IRF8hi and IRF8lo-expressing subtypes improves prognostic significance in breast cancer. Altogether, we posit that separation of TAMs into subtypes reflecting distinct IRF8-reactivities will not only offer a mechanistic basis for their functional diversity, but also illuminate new ways to track patient outcomes.