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

基本信息

批准号：
9356480
负责人：
Jens Marc Titze
金额：
$ 5.9万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9356480
关键词：
4T1 Academic Medical Centers African African American Anti-Inflammatory Agents Anti-inflammatory Asian Indian Bioinformatics Biometry Breast Cancer Model CD3 Antigens CD4 Positive T Lymphocytes CTLA4 gene Cancer cell line Cell Culture Techniques Cell Proliferation Cells Chronic Clinical Collaborations Coupled Data Development Diet Effectiveness 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 Injectable Interleukin-10 Interleukin-17 Laboratories Lead Learning Link Magnetic Resonance Imaging Malignant Neoplasms Mediating Mediator of activation protein Molecular Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Outcome Study Pathology Patients Phase Phenotype Play Proteins Recruitment Activity 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 Universities Up-Regulation Vascular Endothelial Growth Factors Woman Work angiogenesis base cancer cell cancer health disparity cancer initiation cancer prevention cell killing common treatment cytokine demographics dietary restriction dietary salt 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 response salt intake triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression

项目摘要

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