Investigating the Genesis of Tumor Immune Microenvironment (TIME) as a function of Inflammation

摘要 乳腺癌中免疫细胞浸润的类型和模式具有越来越重要的临床意义，因为它们与乳腺癌的发生有关。 对治疗有反应，是免疫治疗的特异性靶点。缺乏浸润性T细胞的“冷”癌症 在乳腺癌中表现出显著的转化生长因子β（TGFβ）活性，并预测预后不良 患者然而，影响肿瘤免疫微环境（TiME）类型发生的因素 还没有被定义。我们发现，在接受放射治疗的女性中， 对于霍奇金淋巴瘤，显著富集缺乏淋巴细胞和富含骨髓细胞的TiME， TGFβ和环氧合酶2。我们使用Trp 53缺失乳腺嵌合体模型来确定 这一意想不到的差异的基础。具有免疫抑制性TiME缺乏淋巴细胞的肿瘤 仅在受辐射的小鼠中出现，即使移植物未受辐射，这表明宿主生物学是关键， 以及缺乏功能性适应性免疫的小鼠，指出先天免疫的作用。引人注目的，短暂的 在癌症形成之前服用阿司匹林可以阻止冷肿瘤的发展。我们假设 全身性炎症引起具有免疫抑制的冷时间ME的肿瘤的发展。慢性低- 由老化、肥胖、压力和病毒感染后的慢性综合征引起的炎症是常见的。这里 我们将检验一个特定的假设，即在癌变过程中炎症诱导的TGFβ改变了组织中的 骨髓细胞，以促进具有免疫抑制性TiME的癌症的发生。AIM 1将使用国家的- 寒冷与肿瘤发生发展相关的细胞因子和免疫特征的分析 使用血液、血浆、骨髓、脾脏和非恶性乳腺的新型生物库的TiME， 在4-、8-和18-时，它们相关的癌症作为炎症或抗炎阿司匹林条件的函数， 治疗后数月。这些发现的相关性将通过乳腺癌患者的免疫分析进行测试。 癌AIM 2将使用联体共生来测试在全身炎症过程中循环的因素是否有助于 使用巨噬细胞耗竭和骨髓细胞不能通过TGFβ传递信号的小鼠来测试是否 循环中TGFβ激活单核细胞，促进冷时ME的发展。AIM 3将分析 使用深度学习和生物信息学方法获得高内容数据，以识别肿瘤亚型， 推断关键事件。我们研究的主要目的是验证炎症诱导的TGFβ 通过在癌发生过程中改变组织驻留的髓样细胞来促进冷肿瘤。我们的提议是 系统的，高内容的分析和建模的机制，乳腺癌的发展， 鉴于TiME的临床重要性日益增加，免疫抑制性TiME是非常重要的。

ABSTRACT The type and pattern of immune cell infiltrate in breast cancer is of growing clinical importance as they associate with response to therapy and are the specific target of immunotherapy. `Cold' cancers that lack infiltrating T cells exhibit pronounced transforming growth factor β (TGFβ) activity and predict poor outcomes in breast cancer patients. However, the factors that influence the genesis of the type of tumor immune microenvironment (TiME) have yet to be defined. We found that radiation-preceded breast cancers in women treated with radiation therapy for Hodgkin's lymphoma are significantly enriched for TiME devoid of lymphocytes and rich in myeloid cells, TGFβ and cyclooxygenase 2. We used a Trp53 null mammary chimera model to determine the factors underpinning of this unexpected difference. Tumors with an immunosuppressive TiME lacking lymphocytes arose only in irradiated mice, even when the transplant was not irradiated, indicating host biology was key, as well as in mice lacking functional adaptive immunity, pointing to a role for innate immunity. Strikingly, transient aspirin treatment before cancer developed blocked the development of cold tumors. We hypothesize that systemic inflammation provokes the development of tumors with immunosuppressive, cold TiME. Chronic low- level inflammation from aging, obesity, stress and chronic syndromes following viral infection is common. Here we will test the specific hypothesis that inflammation-induced TGFβ during carcinogenesis alters tissue-resident myeloid cells to promote the genesis of cancers with an immunosuppressive TiME. AIM 1 will use state-of-the- art analysis of cytokines and immune characteristics that correlate with the development of tumors with cold TiME using a novel biobank of blood, plasma, bone marrow, spleen, and nonmalignant mammary glands and their associated cancers as a function of inflammation or anti-inflammatory aspirin conditions at 4-, 8- and 18- months post-treatment. The relevance of these findings will be tested by immunoprofiling women with breast cancer. AIM 2 will use parabiosis to test whether factors circulating during systemic inflammation contribute and use macrophage depletion and a mouse in which myeloid cells cannot signal through TGFβ to test whether circulating TGFβ elicits monocyte activation to promote the development of cold TiME. AIM 3 will analyze the resulting high-content data using deep learning and bioinformatics methods to identify tumor subtypes and to infer key events. The main goal of our study is to test the innovative hypothesis that inflammation-induced TGFβ promotes cold tumors by altering tissue-resident myeloid cells during carcinogenesis. Our proposal to conduct systematic, high content analysis and modeling of the mechanisms by which breast cancers develop with an immunosuppressive TiME is highly significant in view of the growing clinical importance of the TiME.