The Role of Stromal Autophagy in Cutaneous Melanoma

基质自噬在皮肤黑色素瘤中的作用

• 批准号: 10183191
• 负责人: Hilary A Coller
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183191
• 关键词: Affect; Aftercare; Allografting; Animals; Antibodies; Antigen Presentation; Antigens; Apoptosis; Autophagocytosis; Autophagosome; BRAF gene; Bone Marrow; CD8-Positive T-Lymphocytes; CTLA4 gene; Catabolic Process; Cell Compartmentation; Cell Line; Cells; Clinical; Clinical Trials; Coculture Techniques; Cutaneous Melanoma; Data; Dendritic Cells; Distant; Distant Metastasis; Drug usage; Effectiveness; Environment; FDA approved; Fibroblasts; Gene Expression Profile; Genes; Genetic; Genetically Engineered Mouse; Genotype; Growth; Human; Hydroxychloroquine; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunofluorescence Immunologic; Incidence; Infiltration; Inflammation; Inflammatory; Link; Liver; Lysosomes; Macrophage Activation; Malignant Neoplasms; Melanocytic nevus; Melanoma Cell; Memory; Metabolic; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular; Monitor; Mus; Mutation; Neoplasm Metastasis; Patients; Phenocopy; Plasma; Plasma Cells; Play; Predisposition; Proteins; Recycling; Reporting; Role; S100A4 gene; Sampling; Spleen; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transplantation; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; anti-tumor immune response; antigen test; cancer cell; cancer therapy; cancer type; cell type; combat; conditional knockout; cytokine; experimental study; fighting; follow-up; immune activation; immune checkpoint; immunological status; improved outcome; in vivo; inhibition of autophagy; inhibitor/antagonist; macrophage; melanoma; mouse model; novel; novel strategies; patient subsets; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; recruit; response; small molecule; transcriptome sequencing; tumor; tumor growth; tumor progression

Project Summary Melanoma is a highly aggressive cancer with a rising incidence and good therapeutic options exist for only a subset of patients. Recent studies have shown that treatment with an autophagy inhibitor can improve outcome for melanoma patients. Recognizing the importance of interactions between cancer cells and the host, we chose to investigate the role of autophagy in the stroma. We discovered a new connection between the metabolic/autophagic state of the host, and the immune response to a tumor. We found that the host fibroblast-rich stroma adjacent to a melanoma have higher levels of autophagy marker LC3 than cells distant from the tumor. Using co-culture models, we discovered that cancer cells induce autophagy in co-cultured fibroblasts in a TGF-β-dependent manner. Orthotopic melanoma allografts showed dramatic growth reduction in genetically-engineered mice in which autophagy protein Atg7 was inactivated in the entire animal, or only in fibroblast specific protein 1 (FSP1)- expressing cells, which includes fibroblasts and immune cells. Tumors grown in Atg7-deficient hosts had lower levels of proliferation and higher levels of apotosis than tumors hosted in control mice. We conclude that Atg7 expression in the host plays an important role in supporting tumor progression. To understand the mechanism through which host Atg7 inactivation affects tumor growth, we performed RNA-Seq analysis of tumors harbored in Atg7-inactivated and control mice and discovered a gene expression signature of inflammation. Analysis of cytokines in the plasma and T cells of Atg7-deficient mice revealed higher levels of Th1 type cytokines and no change in Th2 type cytokines. Memory CD4+ and CD8+ T cells from Atg7-deficient mice transitioned from naïve to effector states. Tumor infiltrating lymphocytes in Atg7-deficient mice contained higher levels of CD8+ T cells than in control mice. Treatment with antibodies that deplete T cells resulted in larger tumors in Atg7-deficient mice when tested in the whole body conditional knockout model or in mice with FSP1-specific autophagy inactivation. We have therefore discovered a new mechanism regulating the immune response to tumors. We will investigate the role for additional cell types in anti-tumor immunity in Atg7-deficient mice, and the role of Atg7 in anti-tumor and anti-antigen effector responses. We will test whether small molecule autophagy inhibitors also induce anti-tumor immunity and whether autophagy inactivation sensitizes mice to immune checkpoint inhibitors. We will also test whether the levels of host autophagy in specific cell types correlates with the extent of immune cell infiltration into melanomas in patient samples. We anticipate our findings will suggest new approaches for activating a patient's immune response to fight cancer.

项目摘要 黑色素瘤是一种高度侵略性的癌症 只有一部分患者显示出使用自噬抑制剂的治疗 改善黑色素瘤患者的结果。 和宿主，我们选择研究自噬在基质中的作用。 我们发现了宿主的代谢/自噬状态与您之间的新联系 对肿瘤的免疫反应。 自噬标记LC3水平高于远离肿瘤的细胞。 发现cancancer细胞以ATGF-β依赖性方式诱导以共培养的成纤维细胞诱导自噬。 原位性黑色素瘤同种异体移植物在遗传引擎的小鼠中显示出巨大的生长修复，其中 自噬蛋白ATG7在整个动物中被灭活，或仅在firoblast特异性蛋白1（FSP1） - 表达细胞，其中包括纤维状体和免疫细胞。 我们得出的结论是较低水平和较高水平的呼吸症 宿主中ATG7表达在支持肿瘤进展中起着重要作用。 为了通过宿主ATG7灭活来了解机制会影响肿瘤的生长，我们进行了 在ATG7灭活和控制小鼠中携带的肿瘤的RNA-seq分析，并发现了一个基因 炎症的表达信号。 高水平的Th1型细胞因子，Th2型细胞因子无变化。 来自ATG7缺乏的小鼠的T细胞从幼稚的状态过渡到有效状态。 ATG7缺乏的小鼠用抗体治疗。 当在全身进行测试时 因此，有条件的敲除模型或FSP1特异性自噬灭活的小鼠 发现了一种调节对肿瘤免疫反应的新机制。 我们将研究ATG7定义小鼠的抗肿瘤免疫中其他细胞类型的作用，并 ATG7在抗肿瘤和抗原效应子反应中的作用。 自噬抑制剂还会诱导抗肿瘤免疫力，以及自噬是否使小鼠无效 免疫检查点抑制剂。 与患者样品中的黑色素瘤浸润的程度相关 调查结果将提出激活患者对抗癌的免疫反应的新方法。