Induction of an Antitumor Immune Response in Patients with Melanoma

黑色素瘤患者抗肿瘤免疫反应的诱导

• 批准号: 7895172
• 负责人: PATRICK HWU
• 金额: $ 101.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-09 至 2015-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895172
• 关键词: Antibodies; Antitumor Response; Antiviral Agents; Automobile Driving; Binding; Cancer Center; Cells; Cellular Immunity; Cessation of life; Clinical; Clinical Research; Clinical Trials; Commit; Complex; Cost Sharing; DNA; Data; Databases; Dendritic Cells; Development; Distant; Distant Metastasis; Doctor of Medicine; Early Endosome; Endocytic Vesicle; Environment; Event; Goals; Immune; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Informatics; Injection of therapeutic agent; Interferon Type I; Interferons; Interleukin-2; Investigation; Laboratories; Lead; Lesion; Letters; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Mus; Myelogenous; Natural Immunity; Natural Killer Cells; Nature; Neoplasm Metastasis; Nucleic Acids; Pathology; Pathway interactions; Patients; Peptides; Physicians; Production; Radiation therapy; Reproduction spores; Role; Sampling; Signal Transduction; Site; Solid; Structure; T cell response; T-Lymphocyte; TLR9 gene; Tissues; Toll-like receptors; Translating; Translations; Tumor-Derived; Vaccines; Viral; Virus; Virus Diseases; Wages; antimicrobial peptide; base; cancer immunotherapy; clinical efficacy; extracellular; immune activation; immunogenic; improved; melanoma; microbial; neoplastic cell; novel; peripheral blood; research study; response; tumor; viral DNA

Tumors are potentially immunogenic. However, they fail to spontaneously induce immune responses capable of^ rejecting tumors. A major reason for this is that the tumor microenvironment lacks adequate innate immune activation required to initiate strong adaptive antitumor immunity. Plasmacytoid dendritic cells (pDCs) are highly specialized in that they sense microbial nucleic acids via intracellular Toll-like receptors. During viral infection, pDCs accumulate in infected tissues and are activated by viral nucleic acids to produce large amounts of type I interferons (IFNs) and generate protective immunity against the virus by activating myeloid dendritic cells, T cells, and natural killer cells. Tumors also contain pDCs but do not provide molecular signals to activate pDCs, although tumors contain self-DNA released in the extracellular environment at high concentrations as a result of increaised turnover of tumor cells. pDCs, though activated by viral nucleic acids, clearly are normally not able to sense tumor-derived DNA and are thus unable to initiate strong innate immune responses. We recently found that pDCs can, in fact, sense and respond to self-DNA when combined with an endogenous peptide called LL37. LL37 can bind to self-DNA 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/self-DNA can interact with Toll like receptor 9 to trigger robust type I IFN production similariy to viral DNA. Because tumors release large amounts of self-DNA and contain pDCs but do not express LL37, our hypothesis for the proposed study described herein is that exogenous LL37 can be used to target tumor-derived self-DNA and convert it into a 'danger signal" that triggers pDC activation and type I IFN production at the tumor site in patients with melanoma. This then induces T-cell-mediated immunity against melanoma by using the same mechanism by which anti-viral-immune responses are induced. Therefore, we will pursue the followinig: Specific Aim 1: Determine the mechanism of anti-tumor immune responses induced by intratumoral LL37 injection in mouse tumor models; Specific Aim 2: Evaluate anti-tumor immune responses and clinical efficacy of intratumoral LL37 injection in patients with melanoma; Specific Aim 3: Improve anti-tumor immune responses and efficacy of intratumoral LL37 injection in mouse tumor models. These studies may lead to principles in cancer immunotherapy that may be vyidely applicable to other cancers.

肿瘤具有潜在的免疫原性。然而，它们不能自发诱导能够排斥肿瘤的免疫应答。其主要原因是肿瘤微环境缺乏启动强适应性抗肿瘤免疫所需的足够先天免疫激活。浆细胞样树突状细胞（pDC）是高度特化的，因为它们通过细胞内Toll样受体感知微生物核酸。 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型干扰素（IFN），并通过激活骨髓树突细胞、T细胞和自然杀伤细胞产生针对病毒的保护性免疫。肿瘤也含有pDC，但不提供分子信号来激活pDC，尽管肿瘤含有由于肿瘤细胞更新增加而在细胞外环境中以高浓度释放的自身DNA。pDC，虽然被激活 通过病毒核酸，显然通常不能感知肿瘤来源的DNA，因此不能启动强的先天免疫应答。我们最近发现，pDC实际上可以在与称为LL 37的内源性肽结合时感知并响应自身DNA。LL 37可以结合至由死亡细胞释放的自身DNA片段以形成聚集体和浓缩结构，其被递送至pDC的早期内体并保留在其内。在这些细胞内区室中，LL 37/自身DNA可以与Toll样蛋白相互作用。 受体9类似于病毒DNA触发稳健的I型IFN产生。因为肿瘤释放大量的自身DNA并含有pDC但不表达LL 37，所以我们对本文所述的所提出的研究的假设是外源性LL 37可用于靶向肿瘤来源的自身DNA并将其转化为“危险信号”，其在黑素瘤患者的肿瘤部位触发pDC活化和I型IFN产生。然后通过相同的机制诱导T细胞介导的抗黑色素瘤免疫 由此诱导抗病毒免疫应答。因此，我们将努力实现以下目标：具体目标1： 确定小鼠肿瘤模型中通过瘤内注射LL 37诱导的抗肿瘤免疫应答的机制;具体目标2：评价黑素瘤患者中瘤内注射LL 37的抗肿瘤免疫应答和临床疗效;具体目标3：提高小鼠肿瘤模型中瘤内注射LL 37的抗肿瘤免疫应答和疗效。这些研究可能会导致癌症免疫治疗的原则，这些原则可能非常适用于其他癌症。