Activation of Intratumoral pDCs by Tumor Self-DNA Coupled with Anti-microbial

肿瘤自身 DNA 联合抗菌药物激活瘤内 pDC

• 批准号: 8135420
• 负责人: Michel Gilliet
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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/8135420
• 关键词: Automobile Driving; Binding; Cancer Patient; Cell Death; Cells; Cellular Immunity; Cessation of life; Clinical Trials; Complex; Coupled; DNA; Data; Dendritic Cells; Dendritic cell activation; Disease; Early Endosome; Endocytic Vesicle; Environment; Event; Future; Immune response; Immunity; In Vitro; Injection of therapeutic agent; Interferons; Investigation; Lead; Mediating; Molecular; Myelogenous; Natural Killer Cells; Nature; Nucleic Acids; Pathway interactions; Patients; Peptides; Production; Signal Transduction; Site; Solid; Structure; T-Lymphocyte; Tissues; Toll-like receptors; Tumor Immunity; Tumor-Derived; Vaccines; Viral; Virus; Virus Diseases; antimicrobial; antimicrobial peptide; base; design; extracellular; immune activation; immunogenic; in vivo; microbial; neoplastic cell; novel; research study; tumor; viral DNA

Tumors are potentially immunogenic; however, they fail to spontaneously induce an immune response capable of rejecting the tumor. A major reason is that the tumor microenvironment lacks adequate innate immune activation required to initiate strong adaptive anti-tumor immunity. Plasmacytoid dendritic cells (pDC) comprise a dendritic cell subset highly specialized in sensing microbial nucleic acids via intracellular Toll-like receptors. During viral infection, pDC accumulate in infected tissues and are activated by viral nucleic acids to produce large amounts of type I IFNs and generate protective immunity against the virus through activation of myeloid DCs, T cells, and NK cells. Tumors also contain pDCs, but do not provide the molecular signals to activate pDCs. Although tumors contain high concentrations of self-DMA released in the extracellular environment as a result of the increased turnover and tumor cell death, it is clear that pDCs, while activated by viral nucleic acids, are normally not able to sense tumor-derived DMA and are thereby unable to initiate a strong innate immune response. We recently found that pDC can, in fact, sense and respond to self-DMA when combined with an endogenous peptide called LL37. LL-37 can bind self-DMA fragments released by dying cells to form aggregates and condensed structures that are delivered to and retained within early endosomes of pDCs. In these intracellular compartments, LL37/DNA can interact with TLR9 to trigger robust type I IFN production similarly to viral DMA. Because tumors release large amounts of self-DMA and contain pDCs but do not express LL37, our hypothesis is that exogenous LL37 can be used to target tumor-derived self-DMA and convert it into a "danger signal" that triggers pDC activation and type I IFN production at the tumor site. This will then induce T-cell mediated immunity against the tumor by the same mechanism by which anti-viral immune responses are induced. Specific Aim 1 will determine whether LL37 can convert self-DMA released by dying tumor cells from being immunologically inert into a trigger of pDC activation to produce type I IFNs. Specific Aim 2 will evaluate whether LL37 mixed with dying tumor cells ex-vivo and injected in-vivo as a vaccine can induce effective T cell-mediated anti-tumor immunity. Specific Aim 3 will assess whether dying tumor cells releasing self-DMA can be targeted by intratumoral injection or systemic administration of LL37 to induce innate immune activation at the tumor site leading to effective anti-tumor immunity. These studies may lead to the design of future clinical trials utilizing LL37 in cancer patients with diffusely metastatic disease.

肿瘤具有潜在的免疫原性;然而，它们不能自发地诱导免疫应答 能够排斥肿瘤。一个主要原因是肿瘤微环境缺乏足够的先天性 启动强适应性抗肿瘤免疫所需的免疫激活。 浆细胞样树突状细胞（Plasmacytoid dendritic cells，pDC）是一类高度特异性的树突状细胞亚群， 核酸通过细胞内Toll样受体。在病毒感染期间，pDC在感染的组织中积累 并被病毒核酸激活以产生大量的I型IFN， 通过激活髓样DC、T细胞和NK细胞产生针对病毒的免疫力。 肿瘤也含有pDC，但不提供激活pDC的分子信号。虽然肿瘤 含有高浓度的自我DMA释放在细胞外环境中的结果，增加 尽管pDC被病毒核酸激活，但它通常不被激活， 能够感知肿瘤衍生的DMA，从而不能启动强的先天免疫应答。我们 最近发现，事实上，pDC可以感知并响应于自身DMA，当与内源性DNA结合时， 一种叫做LL 37的肽。LL-37可以结合由垂死细胞释放的自身DNA片段以形成聚集体， 被递送到pDC的早期内体并保留在其内的浓缩结构。在这些 在细胞内区室中，LL 37/DNA可以与TLR 9相互作用以类似地触发稳健的I型IFN产生 到病毒DNA 由于肿瘤释放大量的自身DNA，并含有pDC但不表达LL 37，我们的研究表明， 假设是外源性LL 37可用于靶向肿瘤来源的自身-DMA并将其转化为 在肿瘤部位触发pDC活化和I型IFN产生的“危险信号”。这将导致 T细胞介导的抗肿瘤免疫通过与抗病毒免疫应答相同的机制 是诱导的。 特异性目标1将确定LL 37是否可以将由垂死肿瘤细胞释放的自身DMA从肿瘤细胞中转化出来。 免疫惰性转化为pDC活化的触发物以产生I型IFN。第2章评价 LL 37与垂死的肿瘤细胞离体混合并作为疫苗体内注射是否可以诱导有效的T细胞增殖， 细胞介导的抗肿瘤免疫。具体目标3将评估死亡肿瘤细胞是否释放自我DMA 可以通过肿瘤内注射或全身施用LL 37来靶向诱导先天性免疫 在肿瘤部位激活，导致有效的抗肿瘤免疫。这些研究可能会导致设计 在具有扩散转移性疾病的癌症患者中利用LL 37的未来临床试验。