Targeting cellular double-stranded RNA homeostasis in breast cancer

靶向乳腺癌细胞双链 RNA 稳态

基本信息

批准号：
10278680
负责人：
Cecil Han
金额：
$ 37.38万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10278680
关键词：
Antigen Presentation Antiviral Agents Biological Biological Assay Breast Breast Cancer Cell CD8-Positive T-Lymphocytes CRISPR/Cas technology Cells Chronic Cytoplasm DNA Damage DNA Methylation Detection Double-Stranded RNA Elements Epigenetic Process Exhibits Family Gene Deletion Gene Expression Genetically Engineered Mouse Genomic Instability Homeostasis Human Immune Immune signaling Immune system Immunocompetent Immunologics Immunomodulators Immunotherapeutic agent Immunotherapy Infiltration Inflammation Innate Immune Response Interferon Type I Interferons Lead Link Luciferases MHC Class I Genes Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mediating Metastatic breast cancer Mitochondria Modification Molecular Mus Normal Cell Oxidative Stress Pathway interactions Production RNA RNA Editing RNA Helicase RNA Processing Regulation Reporting Role STAT1 gene Signal Transduction Somatic Cell Source Structure System Therapeutic Transcriptional Silencer Elements Tumor Immunity Virus Diseases anti-PD1 antibodies anti-cancer aspartylglutamate base cancer cell cancer immunotherapy cancer therapy cellular targeting conditional knockout crosslinking and immunoprecipitation sequencing experimental study glutamylalanine helicase human disease immune activation immune checkpoint blockade immunogenic immunogenicity inhibitor/antagonist innate immune sensing knock-down malignant breast neoplasm mouse model new therapeutic target novel overexpression pathogen promoter response sensor small molecule inhibitor therapeutic target transcriptomics tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

Summary/Abstract The immunologically inactive (cold) tumor is a major challenge for effective immunotherapies in many cancers, including breast cancer. Increasing evidence has demonstrated that human cells express various types of endogenous double-stranded RNAs (dsRNAs) regardless of pathogen invasion, and aberrant accumulation of cellular dsRNAs could trigger a detrimental innate immune response in cells. In cancer, these endogenous immunogenic dsRNAs are suggested as a source of immune induction to increase tumor response to immunotherapy. However, to exploit the cellular dsRNAs in immunotherapy for cancer, we need to understand the molecular mechanism for cellular dsRNA homeostasis in normal and malignant cells and find the specific ways to modulate immunogenic dsRNAs. We found that inhibition of DEAD-box RNA helicase 3X (DDX3X) resulted in the cytoplasmic accumulation of endogenous dsRNAs in the breast cancer cells. Loss of DDX3X increased the type I interferon production, STAT1 activation, IFN-stimulated genes (ISGs) expression, and the MHC class I expression with the enhanced antigen presentation on the breast cancer cells. DDX3X inhibition also suppressed the tumor growth and increased the tumor infiltration of active CD8+ T cells and DC in the syngeneic breast cancer mouse model. We hypothesize that inhibiting DDX3X leads to aberrant accumulation of endogenous dsRNAs, which triggers type I IFN responses and induces an innate immune response in the tumor. The proposed studies will be focused on understanding the molecular mechanism by which DDX3X regulates cellular dsRNA homeostasis, providing a link between cellular dsRNAs and immune signals in breast cancer cells, and establishing novel immunotherapeutic strategies for breast cancer. In Aim 1, we will determine the molecular mechanism by which DDX3X regulates cellular dsRNAs; In Aim 2, we will study DDX3X-dsRNAs-Type I IFN axis in cancer cells and human tumor; In Aim 3, we will explore the effect of inhibiting DDX3X to increase anti-tumor immunity and sensitize tumors to immunotherapy. Our study will reveal a novel regulatory mechanism of endogenous dsRNAs in cancer and may lead to novel therapeutics targeting DDX3X for new combinatory immunotherapy.

摘要/摘要免疫学上无活性（冷）肿瘤是许多癌症有效免疫疗法的主要挑战，包括乳腺癌。越来越多的证据表明，人类细胞表达了各种类型的内源性双链RNA（DSRNA），无论病原体入侵如何细胞DSRNA可能会引发细胞中有害的先天免疫反应。在癌症中，这些内源性建议将免疫原性DSRNA作为免疫诱导来源，以增加肿瘤对免疫疗法。但是，要利用免疫疗法中的细胞DSRNA进行癌症，我们需要了解正常和恶性细胞中细胞DSRNA稳态的分子机制，找到特定调节免疫原性DSRNA的方法。我们发现抑制死盒RNA解旋酶3X（DDX3X）导致内源性DSRNA在乳腺癌细胞中的细胞质积累。 DDX3X的损失增加了I型干扰素产生，STAT1激活，IFN刺激的基因（ISGS）表达和 MHC I类表达具有增强的乳腺癌细胞上的抗原表现。 DDX3X抑制还抑制了肿瘤的生长并增加了活性CD8+ T细胞和DC的肿瘤浸润合成性乳腺癌小鼠模型。我们假设抑制DDX3X会导致异常积累内源性DSRNA，它触发I型IFN反应并诱导先天性免疫反应瘤。拟议的研究将集中于理解DDX3X的分子机制调节细胞DSRNA稳态，提供细胞DSRNA和乳房中的免疫信号之间的联系癌细胞，并为乳腺癌建立新的免疫治疗策略。在AIM 1中，我们将确定DDX3X调节细胞DSRNA的分子机制；在AIM 2中，我们将学习癌细胞和人类肿瘤中的DDX3X-DSRNA型I IFN轴；在AIM 3中，我们将探讨抑制DDX3X以增加抗肿瘤免疫力并使肿瘤对免疫疗法敏感。我们的研究将揭示内源性DSRNA在癌症中的新型调节机制，可能导致新的治疗剂靶向新组合免疫疗法的DDX3X。