Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression

定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹

• 批准号: 10012769
• 负责人: Anil Shanker
• 金额: $ 7.57万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012769
• 关键词: 4T1; Academic Medical Centers; African; African American; Anti-Inflammatory Agents; Asian Indian; Bioinformatics; Biometry; Breast Cancer Model; Breast Cancer cell line; CD3 Antigens; CD4 Positive T Lymphocytes; CTLA4 gene; Cell Culture Techniques; Cell Proliferation; Cells; Chronic; Clinical; Collaborations; Coupled; Data; Development; Diet; Effector Cell; Environment; Etiology; Event; Exposure to; FOXP3 gene; Fostering; Gene Expression Profile; Genomics; Grant; Growth; Hispanics; Human; Imaging Techniques; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immunologic Surveillance; Immunologic Techniques; Immunosuppression; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-17; Laboratories; Lead; Learning; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Monoclonal Antibodies; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Outcome Study; Pathology; Patients; Phase; Phenotype; Play; Proteins; Regulatory T-Lymphocyte; Research; Resistance; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Sodium-Restricted Diet; Students; T-Lymphocyte; Tennessee; Testing; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Tissues; Tumor Tissue; Tumor stage; Tumor-Derived; Tumor-infiltrating immune cells; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Woman; Work; angiogenesis; anti-CTLA4; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; base; breast cancer progression; cancer cell; cancer health disparity; cancer initiation; cancer prevention; cell killing; checkpoint therapy; common treatment; cytokine; demographics; dietary restriction; dietary salt; effectiveness evaluation; exhaustion; experience; high risk; imaging modality; imaging study; immune activation; immune checkpoint; immune clearance; immunoregulation; in vivo; inflammatory milieu; inhibitor/antagonist; innovation; macrophage; malignant breast neoplasm; medical schools; monocyte; mouse model; nano-string; neoplastic cell; novel; preclinical study; programmed cell death protein 1; recruit; response; salt intake; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Summary Chronic inflammatory milieu and compromised T-cell immune-surveillance in the tumor microenvironment is suggested to play a decisive role in cancer progression and metastasis. Although various immune effector cells are recruited to the tumor site, their anti-tumor function is down-regulated in response to signals derived from the tumor microenvironment. However, the precise molecular signals for this mechanism remain poorly characterized. Our preliminary studies have demonstrated that stimulation of naive human CD4+T cells and monocytes with high NaCl concentrations (0.2 M) resulted in a temporal-dependent bimodal effect on IL-17 secretion, with an initial increase (1-3 days), followed by a decrease in IL-17 secretion (5-7 days), and an increase in anti- inflammatory IL-10 secretion. This later phase decrease in IL-17 after exposure to high salt is accompanied by enhanced activation of immune-suppressive Tregs(CD4+Foxp3+) and MΦ2-like macrophages, along with up-regulation of immune exhaustion markers (CTLA4, PD1, Tim3, LAG3) in CD4+T cells. Thus, we hypothesize that high-salt concentration in the tumor microenvironment is linked to modulation of IL-17, resulting in tumor growth with immune-exhaustion and immune-suppression responses. These events lead to a dysfunctional late phase effector immune-elimination, culminating to enhance cancer progression and metastasis. Using murine breast cancer models where mice are fed a diet with varying salt content, we will utilize advanced sodium(Na23)-MRI and immunological techniques to test this hypothesis with the following two specific aims: (1) Define and characterize the temporal effect on the functional changes in infiltrating Treg (CD4+FoxP3+IL-10+T cells), Th17(CD4+IL-17+T cells), and macrophages (MΦ1/MΦ2 switch) leading to breast cancer progression; (2) Define the role of immune check-point inhibitors, CTLA4 and PD1 mAb, in high salt-mediated tumor progression compared to checkpoint inhibitor therapy combined with a low-salt diet in two mouse models of breast cancer. We envision that the outcomes of this study will help delineate the molecular mechanisms involved in high salt-mediated dysfunction of immune responses in the tumor microenvironment with a potential clinical translational relevance of lowering salt tissue levels in patients undergoing treatment with immune-check point inhibitors. !

概括 慢性炎症环境和肿瘤微环境中T细胞免疫监视的受损是 建议在癌症进展和转移中发挥决定性作用。虽然各种免疫效应器 细胞被募集到肿瘤部位，其抗肿瘤功能因源自得出的信号而下调 来自肿瘤微环境。但是，该机制的精确分子信号仍然很差 特征。我们的初步研究表明，幼稚的人CD4+T细胞和 NaCl浓度高的单核细胞（0.2 m）导致对IL-17的暂时依赖性双峰作用 分泌，最初增加（1-3天），然后减少IL-17分泌（5-7天），而 抗炎IL-10分泌的增加。暴露于高盐后IL-17的此后期减少 通过增强免疫抑制Treg（CD4+FOXP3+）和Mφ2样的激活来实现 巨噬细胞以及CD4+T中的免疫耗尽标记（CTLA4，PD1，TIM3，LAG3）的上调 细胞。这，我们假设肿瘤微环境中的高盐浓度与 IL-17的调节，导致肿瘤生长，并具有免疫障碍和免疫抑制反应。 这些事件导致功能失调的后期效应子免疫灭绝，最终提高癌症 进展和转移。使用鼠类乳腺癌模型，其中小鼠用不同的盐喂食饮食 内容，我们将利用高级钠（NA23）-MRI和免疫学技术来检验此假设 以以下两个特定目标：（1）定义并表征对功能变化的临时影响 在浸润Treg（CD4+FOXP3+IL-10+T细胞）中，TH17（CD4+IL-17+T细胞）和巨噬细胞（Mφ1/Mφ2 切换）导致乳腺癌进展； （2）定义免疫切解点抑制剂CTLA4的作用 与检查点抑制剂疗法相比，在高盐介导的肿瘤进展中，PD1 mAB 在两种小鼠的乳腺癌模型中，饮食低盐。我们设想这项研究的结果将 帮助描绘出在高盐介导的免疫反应功能障碍中涉及的分子机制 具有降低盐组织水平的潜在临床翻译相关性的肿瘤微环境 接受免疫切除点抑制剂治疗的患者。 呢