Dendritic Cell Proteoglycans and Reprogramming Cancer Immunity

树突状细胞蛋白聚糖和重编程癌症免疫

• 批准号: 10045943
• 负责人: MARK M FUSTER
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045943
• 关键词: Activities of Daily Living; Address; Affect; Anabolism; Antigen Presentation; Antigens; Antisense Oligonucleotides; Area; Binding; CCL21 gene; CD8-Positive T-Lymphocytes; CX3CL1 gene; CXCL12 gene; Cancer Model; Cancer Patient; Carbohydrates; Carcinoma; Cell Communication; Cell Maturation; Cell physiology; Cell surface; Cells; Chest; Clinical; Complex; Cytolysis; Dendrites; Dendritic Cells; Dendritic cell activation; Dendritic cell tumor; Development; Disease remission; Drug Design; Enzymes; Equilibrium; Eye; Genetic; Goals; Growth; Heparan Sulfate Biosynthesis; Heparitin Sulfate; Human; Immune; Immune Tolerance; Immunity; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; KRAS2 gene; Kinetics; Lead; Lewis Lung Carcinoma; Lewis lung carcinoma cell; Lung Neoplasms; Lymphatic; Lymphatic Endothelium; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Ovalbumin; Ovum; Pathologic; Pathway interactions; Patients; Phenotype; Polysaccharides; Preparation; Primary Neoplasm; Production; Property; Proteoglycan; Regulatory T-Lymphocyte; Signal Transduction; Sulfate; Surface; T cell response; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Translations; Tumor Antigens; Tumor Immunity; Ursidae Family; Validation; Work; anti-cancer; base; cell behavior; cell motility; chemokine; chemokine receptor; cytokine; draining lymph node; effector T cell; immune function; improved; inhibitor/antagonist; lung Carcinoma; lymphatic vessel; lymphocyte proliferation; migration; mimetics; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; programs; proteoglycan core protein; receptor; response; scaffold; small molecule inhibitor; sugar; syndecan; targeted agent; trafficking; tumor; tumor growth; tumor microenvironment; tumor progression

Early in cancer growth, metastases and dendritic cells (DCs) traffic to draining lymph nodes (DLN). In lung cancer and other carcinomas, immune-suppression dominates a tumor microenvironment characterized by immature DCs, weak T-effector responses, proliferation of T-regulatory cells (Tregs), and over-production of immuno-suppressive cytokines. This heavily represses anti-tumor immunity. A high-impact area of new scientific discovery is immunotherapy. We find dramatic clinical responses in some advanced-stage cancer patients by blocking suppression of effector T cells. Only a fraction (<25%) of such patients, however, respond with durable remissions. Preliminary work shows that a unique class of glycans known as heparan sulfate (HS) drives subversive DC traffic and DC immaturity. While we have inhibited such DC traffic by targeting lymphatic endothelial HS, new work suggests that DC-specific HS alterations may modulate both pathologic chemokine- dependent DC traffic as well as DC maturation and function. New studies also show that these properties may favorably impact anti-tumor T cell functions, with inhibition of tumor growth and progression. Herein we target such glycans in tumor and cell-based studies, while studying immune-function and molecular mechanisms. This proposal addresses the hypothesis that targeting HS glycans on the surface of DCs in lung cancer through genetic means and novel inhibitors will inhibit DLN colonization by tolerogenic DCs and improve anti- tumor immunity. Reduced immune-tolerance and improved tumor-antigen responses by more mature DCs, with improved T cell induction will result in a novel endogenous anti-tumor state. To test this, we propose to: (1) Characterize tumor growth and anti-tumor immunity in model antigen- as well as spontaneous lung carcinoma models in mice bearing DC-glycan alterations. We will assess how a DC-targeted mutation in a key sulfating HS biosynthetic enzyme (Ndst1) affects T cell immunity in tumors and thoracic DLN of mice with orthotopic Ovalbumin-expressing Lewis lung carcinomas (LLC-Ova), including Ova-specific immunity and effects on tumor growth. Immunity and tumor growth in a KRAS transgenic mutant model will also be studied. (2) Study anti-tumor DC and T cell functions in ex-vivo preparations from lung carcinoma bearing mice with DC-specific alterations in HS biosynthesis. DC maturation, antigen presentation, and the capacity of DCs from LLC-Ova tumors grown in DC-targeted HS mutants to activate Ova-sensitized T cells will be examined, as will tumor-cytolytic capacity of CD8+ T cells isolated from DLNs of tumor-bearing mutant vs control mice. Studies will also include the effects of mutation on DLN colonization by plasmacytoid DCs and their functional capacity. (3) Assess chemokine-receptor interactions and signaling mechanisms in the setting of DC-targeted alterations in HS biosynthesis; and the effects of novel HS inhibitors on tumor growth and immunity. We will study how HS mutation affects DC-surface binding of lymphatic chemokines CCL21, CXCL12, or CX3CL1 to cognate receptors. The effect of HS mutation on DC migration and maturation signaling in response to chemokine will be assessed, including the activation of pDCs through novel TLR-dependent mechanisms. Finally, we will study how novel HS inhibitors affect signaling by tumor DCs as well as lung carcinoma growth and immunity. This work examines novel mechanisms whereby altering trafficking and maturation of tumor DCs may effectively re-program endogenous anti-tumor immunity. The genetic target validation and rational introduction of glycan-targeting inhibitors may guide new therapies to achieve immune eradication of human lung cancer.

在癌症生长，转移和树突状细胞（DCS）流量的早期，流动淋巴结（DLN）。在肺部 癌症和其他癌，免疫抑制主导着以肿瘤微环境为特征 未成熟的DC，弱T-效应反应，T调节细胞的增殖（Tregs）以及过量产生 免疫抑制细胞因子。这严重抑制了抗肿瘤的免疫力。新的高影响区域 科学发现是免疫疗法。我们发现某些晚期癌症中的临床反应显着 通过阻止抑制效应T细胞的患者。但是，只有一小部分（<25％）此类患者做出回应 持久的解雇。初步工作表明，一类称为硫酸乙酰肝素（HS）的独特类的聚糖 驱动颠覆性直流交通和直流不成熟。虽然我们通过靶向淋巴管抑制了此类直流流量 内皮HS，新工作表明，直流特异性HS改变可能会调节这两种病理趋化因子 - 依赖的直流流量以及直流的成熟和功能。新研究还表明，这些特性可能 有利影响抗肿瘤T细胞功能，并抑制肿瘤生长和进展。我们在此目标 在研究免疫功能和分子机制的同时，在肿瘤和基于细胞的研究中进行了这种聚糖。 该提议解决了以下假设：靶向HS聚糖在肺癌表面上 通过遗传手段和新型抑制剂将抑制耐受性DC的DLN定殖，并改善抗抗 肿瘤免疫。更成熟的DC降低了免疫耐受性并改善了肿瘤抗原反应， 随着T细胞诱导的改善，将导致新型的内源性抗肿瘤状态。为了测试这一点，我们建议： （1）表征模型抗原和自发肺中肿瘤生长和抗肿瘤免疫力 带有直流聚糖改变的小鼠的癌模型。我们将评估钥匙中的DC靶向突变 硫酸HS生物合成酶（NDST1）影响小鼠肿瘤和胸腔DLN的T细胞免疫力 原位表达狮子蛋白的原位卵巢肺癌（LLC-OVA），包括OVA特异性免疫力和 对肿瘤生长的影响。还将研究KRAS转基因突变体模型中的免疫和肿瘤生长。 （2）研究抗肿瘤的DC和T细胞功能在带有肺癌小鼠的肺癌的前体内制剂中 HS生物合成的直流特异性改变。 DC成熟，抗原表现和DC的能力 将检查以DC靶向的HS突变体生长的LLC-OVA肿瘤，以激活OVA敏化的T细胞，并将检查 从肿瘤突变体与对照小鼠的DLN分离的CD8+ T细胞的肿瘤 - 细胞溶解能力。研究 还将包括突变对浆细胞类动物DC及其功能能力的DLN定植的影响。 （3）评估趋化因子 - 受体相互作用和信号传导机制在dc靶向改变的情况下 在HS生物合成中；新型HS抑制剂对肿瘤生长和免疫力的影响。我们将研究HS 突变影响淋巴趋化因子CCL21，CXCL12或CX3CL1的直流表面结合与同源 受体。 HS突变对DC迁移和响应趋化因子的成熟信号的影响将会 可以评估，包括通过新型TLR依赖性机制激活PDC。最后，我们会的 研究新型HS抑制剂如何影响肿瘤DC以及肺癌生长和免疫力的信号传导。 这项工作研究了新的机制，从而改变肿瘤DC的运输和成熟 有效地重新编程内源性抗肿瘤免疫。遗传目标验证和理性介绍 靶向聚糖的抑制剂可以指导新疗法以实现人类肺癌的免疫消除。