The role of Toll-like receptor 3 in overcoming cancer immunoediting

Toll 样受体 3 在克服癌症免疫编辑中的作用

• 批准号: 7383695
• 负责人: Jessica K Bell
• 金额: $ 16.05万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383695
• 关键词: Active Immunotherapy; Adjuvant; Affinity; Agonist; Antigen-Presenting Cells; Antigens; Apoptosis; Binding; Biochemical; Biological; Biological Assay; C57BL/6 Mouse; Cancer Vaccines; Cell Survival; Cells; Class; Complex; Data; Dendritic Cells; Development; Double Effect; Double-Stranded RNA; Enzyme-Linked Immunosorbent Assay; Equilibrium; Face; Gel Chromatography; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunotherapy; Inflammatory Response; Interferon Type I; Interleukin-6; Kinetics; Knowledge; Libraries; Ligand Binding; Ligand Binding Domain; Ligands; Lipids; Malignant Neoplasms; Mediating; Melanoma Cell; Methods; Modeling; Molecular; Monitor; Mus; Pathway interactions; Pattern; Pattern recognition receptor; Production; Property; Public Health; RNA; RNA Binding; Research; Research Personnel; Role; Site; Specificity; Splenocyte; Structure; Surface Plasmon Resonance; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Tumor Escape; Vaccinated; Vaccine Adjuvant; Vaccines; Variant; Viral; Work; activating transcription factor; analytical ultracentrifugation; anticancer research; bacterial genetics; base; cancer cell; cancer immunotherapy; cytokine; enzyme linked immunospot assay; human TLR3 protein; immunogenic; immunogenicity; improved; in vivo; monocyte; mouse model; mutant; neoplastic cell; novel; pathogen; programs; receptor; research study; response; size; stoichiometry; tumor

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop immune modulators that activate a potent immune response leading to the elimination of human cancer cells. Cancer immunotherapy directs the power of the immune system to select for and eliminate tumor cells. In doing so, tumor variants that are not immediately removed battle with the immune system in a dynamic equilibrium of tumor destruction and tumor escape. From this Darwinian-type selection, tumor variants arise that have reduced immunogenicity and grow into clinically apparent tumors. To reestablish immunogenicity, immune cells must regain the ability to sense tumor escape variants. Immune cells can be stimulated by microbially-derived ligands via pathogen recognition receptors, like toll-like receptors (TLRs). TLRs can respond to diverse ligands such as bacterial lipid coat components to viral or bacterial genetic material. My immediate research goal is to understand how TLRs recognize their diverse class of ligands and use this knowledge to develop therapeutic molecules that stimulate, or even inhibit, the immune system. My initial target is toll-like receptor 3 (TLR3), which recognizes double stranded RNA (dsRNA). My hypothesis is that by unraveling the molecular interactions between TLR3 and its dsRNA ligand, the necessary components of a potent immune modulator, such as a vaccine adjuvant, will be defined. The studies use a combination of biochemical, biophysical and biological approaches to define ligand interactions with the receptor and their subsequent effect on immune and cancer cells. Specifically, mutational analysis, cell-based assays and structural analysis of the TLR3:dsRNA complex will further refine our model of ligand recognition. In addition, TLR3 binding to a ligand library will be characterized via gel filtration, ELISA, analytical ultracentrifugation and surface plasmon resonance. Biochemical parameters of ligand binding will be correlated to immune cell stimulation and cancer cell survival. In vivo adjuvant potential of TLR3 ligands will be assessed in a mouse model by antigen-specific T cell production and tumor reduction. The pairing of structure, biochemical and biological experiments will reveal how TLR3 ligands can be used as a switch to wield the power of the immune system. This work will improve public health by developing a vaccine adjuvant that will increase the efficacy of human cancer vaccines and provide a direct, novel therapy for human cancers expressing TLR3.

描述（由申请人提供）：本研究的长期目标是开发免疫调节剂，激活有效的免疫反应，从而消除人类癌细胞。癌症免疫疗法引导免疫系统的力量来选择和消除肿瘤细胞。在这样做的过程中，没有被立即去除的肿瘤变体在肿瘤破坏和肿瘤逃逸的动态平衡中与免疫系统进行斗争。从这种达尔文型选择中，产生了免疫原性降低的肿瘤变体，并生长成临床上明显的肿瘤。为了重建免疫原性，免疫细胞必须重新获得感知肿瘤逃逸变体的能力。免疫细胞可以通过病原体识别受体（如toll样受体（TLR））被微生物来源的配体刺激。TLR可以响应于不同的配体，如细菌脂质外壳组分，以病毒或细菌遗传物质。我的近期研究目标是了解TLR如何识别其不同类型的配体，并利用这些知识开发刺激甚至抑制免疫系统的治疗分子。我最初的目标是Toll样受体3（TLR3），它识别双链RNA（dsRNA）。我的假设是，通过解开TLR3和它的dsRNA配体之间的分子相互作用，一个有效的免疫调节剂，如疫苗佐剂的必要组成部分，将被定义。这些研究使用生物化学，生物物理和生物学方法的组合来定义配体与受体的相互作用及其对免疫和癌细胞的后续影响。具体而言，突变分析，基于细胞的测定和TLR3：dsRNA复合物的结构分析将进一步完善我们的配体识别模型。此外，TLR3与配体文库的结合将通过凝胶过滤、ELISA、分析性超离心和表面等离子体共振来表征。配体结合的生化参数将与免疫细胞刺激和癌细胞存活相关。将在小鼠模型中通过抗原特异性T细胞产生和肿瘤减少来评估TLR3配体的体内佐剂潜力。结构，生化和生物学实验的配对将揭示TLR3配体如何被用作开关来发挥免疫系统的力量。这项工作将通过开发一种疫苗佐剂来改善公众健康，这种佐剂将增加人类癌症疫苗的功效，并为表达TLR3的人类癌症提供直接的新型疗法。