Pathobiology of Interferon-gamma in UV radiation-induced melanomagenesis

干扰素-γ在紫外线辐射诱导的黑色素瘤发生中的病理学

• 批准号: 9193631
• 负责人: M. Raza Zaidi
• 金额: $ 35.69万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-10 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193631
• 关键词: Ablation; Alzheimer disease prevention; BRAF gene; Biological Markers; Cell Line; Cell-Mediated Cytolysis; Cells; Clinic; Clinical; Cutaneous Melanoma; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Disease Progression; Drug resistance; Epidemic; Exposure to; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Goals; Human; IFNGR1 gene; Immunosuppression; Immunotherapy; Incidence; Induced Mutation; Inflammation; Inflammatory; Interferon Type II; Knock-out; Knockout Mice; Label; Link; LoxP-flanked allele; Lung; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Neoplasm to the Lung; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Predisposition; Preventive; Process; Recruitment Activity; Research; Resistance; Risk Factors; Role; Sampling; Signal Transduction; Skin; Skin Cancer; Stat3 protein; Suppressor Genes; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; The Sun; Therapeutic; Tumorigenicity; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; Up-Regulation; Validation; Woman; cytokine; experimental study; in vivo; inhibitor/antagonist; irradiation; knock-down; macrophage; melanocyte; melanoma; melanoma biomarkers; microphthalmia-associated transcription factor; mouse model; mutant; mutant mouse model; novel; novel strategies; outcome forecast; overexpression; personalized immunotherapy; personalized management; potential biomarker; predictive marker; public health relevance; response; response biomarker; therapeutic target; treatment strategy; tumor; tumor microenvironment; tumorigenic; ultraviolet damage; ultraviolet irradiation

 DESCRIPTION (provided by applicant): Cutaneous malignant melanoma is one of the most common and deadliest cancers, and its incidence continues to rise to epidemic proportions, to the extent that it is now the most prevalent cancer among women under forty. The solar ultraviolet radiation (UV) is widely accepted to be the greatest risk factor for melanoma; however, the underlying molecular mechanisms are incompletely understood. Identification of the causal UV-induced mutations has long been the major thrust in the field, but importance of non-mutational and microenvironmental mechanisms, for example inflammation and immunoevasion/immunosuppression, remains severely understudied. Here we have proposed a hypothesis that Interferon-gamma (IFNg), which is conventionally associated with anti-tumor immunesurveillance mechanisms, plays a pro-tumorigenic role in the context of UV-induced melanomagenesis. The proposed research will elucidate the mechanisms of the pro-melanomagenic effects of IFNg. In Specific Aim 1, the specific mechanisms of the pro-metastatic and drug resistance effects of IFNg treatment on melanoma cells via activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Microphthalmia Associated Transcription Factor (MITF) will be tested. UV- induced melanomagenesis experiments will be performed in the inducible BrafV600E (BrafCA)mouse model of UV-induced melanomagenesis, in which the IFNg signaling has been blocked via melanocyte-specific knockout of IFNg-Receptor. Specific Aim 2 will characterize the IFNg-secreting (IFNg+) macrophages that are recruited to the skin microenvironment by erythemal UV exposure, and will validate this novel subpopulation of macrophages as a biomarker of susceptibility and prognosis of human melanoma. It will be determined whether genetic blockade of UV-induced macrophage influx into skin inhibits melanomagenesis. In Specific Aim 3, the role of IFNg-induced expression of the cytotoxic T-lymphocyte antigen 4 (CTLA4) in melanoma cells in the process of melanomagenesis will be investigated. It will be tested whether melanocytic expression of CTLA4 protects them from T-cell-mediated immunesurveillance, leading to immunoevasion and progression of melanoma, and whether genetic ablation of Ctla4 specifically in the melanocyte compartment inhibits UV-induced melanomagenesis in the BrafCA mouse model. Finally, CTLA4 expression on melanoma cells will be investigated as a predictive biomarker of response to anti-CTLA4 immunotherapy in clinical samples of human melanoma patients. The overall goal of the proposed project is to investigate the IFNg pathway as a novel microenvironmental mechanistic link to UV-induced melanoma susceptibility and disease progression.

 描述(申请人提供)：皮肤恶性黑色素瘤是最常见和最致命的癌症之一，其发病率继续上升到流行的比例，以至于它现在是40岁以下女性中最常见的癌症。太阳紫外线辐射(UV)被广泛认为是黑色素瘤的最大危险因素；然而，其潜在的分子机制尚不完全清楚。鉴定紫外线诱变的原因一直是该领域的主要研究方向，但非突变和微环境机制的重要性，例如炎症和免疫逃避/免疫抑制，仍然严重缺乏研究。在这里，我们提出了一种假说，即干扰素-γ(IFNG)在紫外线诱导的黑色素瘤发生中起促肿瘤作用，通常与抗肿瘤免疫监视机制有关。这项拟议的研究将阐明IFNG促黑色素瘤作用的机制。在特定的目标1中，将测试IFNG通过激活信号转导和转录激活因子3(STAT3)和微眼病相关转录因子(MITF)对黑色素瘤细胞的促转移和耐药作用的具体机制。紫外线诱导的黑色素瘤发生实验将在可诱导的BRAFV600E(BrafCA)小鼠模型中进行，在该模型中，IFNG信号已通过黑素细胞特异性的IFNG受体敲除而被阻断。具体目标2将描述通过红斑紫外线照射而被招募到皮肤微环境中的分泌IFNG+的巨噬细胞的特征，并将验证这一新的巨噬细胞亚群作为人类黑色素瘤易感性和预后的生物标志物。将确定基因阻断紫外线诱导的巨噬细胞进入皮肤是否抑制黑色素瘤的发生。在特定目标3中，将研究干扰素诱导黑色素瘤细胞表达细胞毒性T淋巴细胞抗原4(CTLA4)在黑色素瘤发生过程中的作用。将测试CTLA4的黑素细胞表达是否保护它们免受T细胞介导的免疫监视，从而导致黑色素瘤的免疫逃避和进展，以及在BrafCA小鼠模型中，特异性地在黑素细胞间进行CTLA4的基因消融是否抑制了紫外线诱导的黑色素瘤的发生。最后，在人类黑色素瘤患者的临床样本中，将研究黑色素瘤细胞上CTLA4的表达作为抗CTLA4免疫治疗反应的预测生物标记物。该项目的总体目标是研究IFNG通路作为一种新的微环境机制与紫外线诱导黑色素瘤易感性和疾病进展的联系。