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：
9211644
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
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/9211644
关键词：
4T1 Academic Medical Centers Accounting African African American Anti-Inflammatory Agents Anti-inflammatory 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 Couples Therapy Data Development Diagnostic Neoplasm Staging Diet Effectiveness Effector Cell Environment Etiology Event Exposure to Fostering Functional disorder Gene Expression Profile Genomics Grant Hispanics Human Imaging Techniques Immune Immune response Immunologic Surveillance Immunologic Techniques Immunosuppression In Vitro Inbred BALB C Mice Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-17 Laboratories Lead Learning Life 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 Staging Students T-Lymphocyte Tennessee Testing The Vanderbilt-Ingram Cancer Center at the Vanderbilt University Tissues Tumor Tissue Tumor stage 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 feeding high risk imaging modality immune activation immune clearance in vivo inhibitor/antagonist innovation macrophage malignant breast neoplasm medical schools monocyte mouse model nano-string neoplastic cell novel preclinical study response salt intake therapy development 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. !

概括肿瘤微环境中的慢性炎症环境和受损的 T 细胞免疫监视是尽管多种免疫效应物在癌症进展和转移中起决定性作用。细胞被招募到肿瘤部位，它们的抗肿瘤功能响应于衍生的信号而下调然而，这种机制的精确分子信号仍然很差。我们的初步研究表明，刺激初始人类 CD4+T 细胞和高 NaCl 浓度 (0.2 M) 的单核细胞对 IL-17 产生时间依赖性双峰效应分泌，最初增加（1-3 天），随后 IL-17 分泌减少（5-7 天），然后暴露于高盐后，抗炎性 IL-10 分泌增加。后期 IL-17 减少。伴随着免疫抑制 Tregs (CD4+Foxp3+) 和 MΦ2 样的增强激活巨噬细胞，以及 CD4+T 中免疫耗竭标志物（CTLA4、PD1、Tim3、LAG3）的上调因此，我们研究了肿瘤微环境中的高盐浓度与细胞的相关性。 IL-17 的调节，导致肿瘤生长并伴有免疫耗竭和免疫抑制反应。这些事件导致晚期效应器免疫消除功能失调，最终加剧癌症使用小鼠乳腺癌模型，给小鼠喂食不同盐的饮食。内容中，我们将利用先进的钠（Na23）-MRI和免疫学技术来检验这一假设具有以下两个具体目标：（1）定义和表征对功能变化的时间影响浸润性 Treg（CD4+FoxP3+IL-10+T 细胞）、Th17（CD4+IL-17+T 细胞）和巨噬细胞（MΦ1/MΦ2 开关）导致乳腺癌进展；（2）定义免疫检查点抑制剂 CTLA4 的作用和 PD1 mAb，与检查点抑制剂联合治疗相比，在高盐介导的肿瘤进展中我们预计这项研究的结果将是在两种乳腺癌小鼠模型中进行低盐饮食。帮助描述高盐介导的免疫反应功能障碍的分子机制肿瘤微环境与降低盐组织水平具有潜在的临床转化相关性接受免疫检查点抑制剂治疗的患者。！