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

研究肿瘤免疫微环境 (TIME) 的起源作为炎症的函数

• 批准号: 10588052
• 负责人: Mary Helen Barcellos-Hoff
• 金额: $ 49.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588052
• 关键词: Affect; Aftercare; Age; Aging; Anti-Inflammatory Agents; Aspirin; BRCA1 gene; Bioinformatics; Biology; Blood; Bone Marrow; Breast Cancer Patient; Breast Cancer Risk Factor; Cell model; Cells; Characteristics; Chimera organism; Chronic; Clinical; Communities; Data; Development; Distal; Dose; Event; Exhibits; Germ-Line Mutation; Goals; Histologic; Hodgkin Disease; Immune; Immune system; Immunotherapy; Infiltration; Inflammation; Lymphocyte; Lymphocytic Infiltrate; Macrophage; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Methods; Modeling; Mus; Myeloid Cells; Natural Immunity; Nature; Non-Malignant; Obesity; Outcome; Parabiosis; Pattern; Phenotype; Plasma; Population; Publishing; Radiation; Radiation therapy; Recording of previous events; Reporter; Role; Second Primary Cancers; Signal Transduction; Spleen; Stress; Syndrome; T cell infiltration; Testing; Tissues; Transforming Growth Factor beta; Transplantation; Tumor Escape; Tumor Immunity; Tumor Subtype; Tumor-Infiltrating Lymphocytes; Virus Diseases; Woman; adaptive immunity; anti-tumor immune response; biobank; cancer immunotherapy; carcinogenesis; clinically significant; conditional knockout; cyclooxygenase 2; cytokine; deep learning; deep learning model; experimental study; high risk population; immune cell infiltrate; immunoregulation; innovation; malignant breast neoplasm; mammary; molecular modeling; monocyte; neoplasm resource; novel; pregnancy-associated breast cancer; response; systemic inflammatory response; treatment response; tumor; tumor-immune system interactions

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.

抽象的 乳腺癌中免疫细胞浸润的类型和模式在关联时越来越重要 对治疗的反应，是免疫疗法的特定靶标。缺乏浸润T细胞的“冷”癌症 暴露了明显转化生长因子β（TGFβ）活性，并预测乳腺癌的结果不佳 患者。但是，影响肿瘤免疫微环境类型的起源的因素（时间） 尚未定义。我们发现在接受放射治疗治疗的女性中，放射线疗法的乳腺癌 对于霍奇金的淋巴瘤，对于没有淋巴细胞的时间而言，淋巴瘤显着富集，并且在髓样细胞中富含 TGFβ和环氧合酶2。我们使用TRP53无效的乳腺嵌合体模型来确定因子 这一意外差异的基础。缺乏淋巴细胞的免疫抑制时间的肿瘤 即使未辐照移植的小鼠，也仅在辐照小鼠中产生，表明宿主生物学是关键，因为 以及在缺乏功能适应性免疫史的小鼠中，指出了先天免疫史的作用。令人惊讶的是，短暂 阿司匹林在癌症发生前的治疗中阻塞了冷肿瘤的发展。我们假设这一点 系统性炎症会引起免疫抑制，寒冷的时间的肿瘤发育。慢性低 - 病毒感染后衰老，肥胖，压力和慢性综合征的水平炎症很常见。这里 我们将测试以下特定假设，即炎症诱导的癌变中的TGFβ会改变组织居民 髓样细胞以免疫抑制时间促进癌症的起源。 AIM 1将使用最新 与冷肿瘤相关的细胞因子和免疫特征的艺术分析 时间使用新型的血液，血浆，骨髓，sleen和非恶性乳腺的时间 它们相关的癌症是4-，8和18-的炎症或抗炎阿司匹林条件的函数 治疗后的月份。这些发现的相关性将通过免疫促进乳房的妇女进行测试 癌症。 AIM 2将使用抛物线症来测试全身注射过程中循环的因素是否有贡献和 使用巨噬细胞部署和小鼠，其中髓样细胞无法通过TGFβ发出信号以测试是否 循环TGFβ引起单核细胞激活以促进寒冷时间的发展。 AIM 3将分析 使用深度学习和生物信息学方法识别肿瘤亚型和TO，产生了高含量数据 推断关键事件。我们研究的主要目的是测试炎症诱导的TGFβ的创新假设 通过在癌变期间改变组织居住的髓样细胞来促进冷肿瘤。我们进行的提议 乳腺癌通过 鉴于当时的临床重要性日益增长，免疫抑制时间非常重要。