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: 9210833
• 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
• 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/9210833
• 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

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. !

总结 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 表明在癌症进展和转移中起决定性作用。尽管各种免疫效应物 当细胞被募集到肿瘤部位时，它们的抗肿瘤功能响应于来源于细胞的信号而下调。 从肿瘤微环境中分离出来然而，这种机制的精确分子信号仍然很差 表征了我们的初步研究表明，刺激幼稚人类CD 4 +T细胞和 高浓度NaCl（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），最后增加 抗炎IL-10分泌增加。在暴露于高盐后IL-17的后期降低 伴随着免疫抑制性T细胞（CD 4 + Foxp 3+）和MΦ2样细胞的激活增强， 巨噬细胞，沿着CD 4 +T细胞中免疫耗竭标志物（CTLA 4、PD 1、Tim 3、LAG 3）的上调 细胞因此，我们假设肿瘤微环境中的高盐浓度与 调节IL-17，导致肿瘤生长伴随免疫耗竭和免疫抑制应答。 这些事件导致功能失调的晚期效应免疫消除，最终增强癌症 进展和转移。使用小鼠乳腺癌模型，其中小鼠被喂食不同盐的饮食 我们将利用先进的钠（Na 23）-MRI和免疫学技术来验证这一假设 具体目标有两个：（1）定义和表征功能变化的时间效应 在浸润性Treg（CD 4 + FoxP 3 +IL-10+T细胞）、Th 17（CD 4 +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CTLA 4的作用 与检查点抑制剂联合治疗相比， 在两个乳腺癌小鼠模型中进行低盐饮食。我们预计，这项研究的结果将 有助于阐明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的潜在临床转化相关性， 接受免疫检查点抑制剂治疗的患者。 !