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具有越来越重要的临床意义，因为它们与 缺乏浸润性 T 细胞的“冷”癌症 表现出转化生长因子 β (TGFβ) 活性并预测乳腺癌的不良预后 然而，影响肿瘤免疫微环境（TiME）类型发生的因素。 我们发现接受放射治疗的女性中发生放射前乳腺癌的情况尚未确定。 对于霍奇金淋巴瘤，TiME 显着富集，缺乏淋巴细胞但富含骨髓细胞， TGFβ和环氧合酶2.我们使用Trp53无效乳腺嵌合体模型来确定因素 具有缺乏淋巴细胞的免疫抑制 TiME 的肿瘤是这种意外差异的基础。 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，因为 以及缺乏功能性适应性免疫的小鼠，表明先天免疫的作用是惊人的、短暂的。 癌症发生前的阿司匹林治疗可阻止冷肿瘤的发展。 全身炎症会通过免疫抑制、冷 TiME 引发肿瘤的发展。 衰老、肥胖、压力和病毒感染后的慢性综合症引起的炎症在这里很常见。 我们将测试以下具体假设：癌发生过程中炎症诱导的 TGFβ 会改变组织驻留 骨髓细胞通过免疫抑制 TiME 促进癌症的发生，AIM 1 将使用最新技术。 与寒冷肿瘤发展相关的细胞因子和免疫特征的艺术分析 TiME 使用血液、血浆、骨髓、脾脏和非恶性乳腺的新型生物库 与 4-、8- 和 18- 炎症或抗炎阿司匹林条件相关的癌症 治疗后几个月，将通过对患有乳腺癌的女性进行免疫分析来测试这些发现的相关性。 AIM 2 将使用联体共生来测试全身炎症期间循环的因素是否有影响。 使用巨噬细胞耗竭和骨髓细胞无法通过 TGFβ 发出信号的小鼠来测试是否 循环 TGFβ 引发单核细胞活化，促进冷 TiME 3 的发展。 使用深度学习和生物信息学方法产生的高内容数据来识别肿瘤亚型并 我们研究的主要目标是检验炎症诱导 TGFβ 的创新假设。 我们的建议是通过在致癌过程中改变组织驻留的骨髓细胞来促进冷肿瘤。 对乳腺癌发生机制进行系统、高内涵的分析和建模 鉴于 TiME 的临床重要性日益增长，免疫抑制 TiME 具有非常重要的意义。