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：
10674720
负责人：
Cecil Han
金额：
$ 36.63万
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/10674720
关键词：
Antigen Presentation Biological Biological Assay 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 Evasion Immune response Immune signaling Immune system Immunocompetent Immunologics Immunomodulators Immunotherapeutic agent Immunotherapy Infiltration Inflammation Innate Immune Response Interferon Type I Interferons Invaded 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 System Therapeutic Transcriptional Silencer Elements Tumor Immunity Viral Virus Diseases anti-PD1 antibodies anti-cancer aspartylglutamate 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 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/摘要免疫不活跃（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，人体细胞表达多种类型的内源性双链 RNA (dsRNA)，无论病原体入侵如何，以及异常积累细胞 dsRNA 可能会引发细胞中有害的先天免疫反应。在癌症中，这些内源性免疫原性 dsRNA 被建议作为免疫诱导的来源，以增加肿瘤对免疫疗法。然而，为了在癌症免疫治疗中利用细胞 dsRNA，我们需要了解正常和恶性细胞中细胞 dsRNA 稳态的分子机制，并找到具体的调节免疫原性 dsRNA 的方法。我们发现 DEAD-box RNA 解旋酶 3X (DDX3X) 的抑制导致乳腺癌细胞中内源性 dsRNA 在细胞质中积累。 DDX3X 丢失增加 I 型干扰素产生、STAT1 激活、IFN 刺激基因 (ISG) 表达以及 MHC I 类表达，乳腺癌细胞上的抗原呈递增强。 DDX3X 抑制还抑制了肿瘤生长并增加了活性 CD8+ T 细胞和 DC 的肿瘤浸润同基因乳腺癌小鼠模型。我们假设抑制 DDX3X 会导致异常积累内源性 dsRNA，触发 I 型 IFN 反应并诱导先天免疫反应瘤。拟议的研究将侧重于了解 DDX3X 的分子机制调节细胞 dsRNA 稳态，提供细胞 dsRNA 和乳腺免疫信号之间的联系癌细胞，并建立新的乳腺癌免疫治疗策略。在目标 1 中，我们将确定 DDX3X 调节细胞 dsRNA 的分子机制；在目标 2 中，我们将学习癌细胞和人类肿瘤中的 DDX3X-dsRNAs-I 型 IFN 轴；在目标 3 中，我们将探讨以下效果：抑制 DDX3X 可增加抗肿瘤免疫力并使肿瘤对免疫治疗敏感。我们的研究将揭示癌症中内源性 dsRNA 的一种新的调节机制，可能会导致新的治疗靶向 DDX3X 用于新的组合免疫疗法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity.

DOI：
10.1186/s12943-023-01892-x
发表时间：
2023-12-13
期刊：
MOLECULAR CANCER
影响因子：
37.3
作者：
Kwon, Juntae;Zhang, Jinmin;Mok, Boram;Allsup, Samuel;Kim, Chul;Toretsky, Jeffrey;Han, Cecil
通讯作者：
Han, Cecil

CK2-Mediated Phosphorylation Upregulates the Stability of USP13 and Promotes Ovarian Cancer Cell Proliferation.

DOI：
10.3390/cancers15010200
发表时间：
2022-12-29
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

A Dual Role of DDX3X in dsRNA-Derived Innate Immune Signaling.

DOI：
10.3389/fmolb.2022.912727
发表时间：
2022
期刊：
Frontiers in molecular biosciences
影响因子：
5
作者：
通讯作者：

Amplification of USP13 drives ovarian cancer metabolism.

DOI：
10.1038/ncomms13525
发表时间：
2016-11-28
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Han, Cecil;Yang, Lifeng;Choi, Hyun Ho;Baddour, Joelle;Achreja, Abhinav;Liu, Yunhua;Li, Yujing;Li, Jiada;Wan, Guohui;Huang, Cheng;Ji, Guang;Zhang, Xinna;Nagrath, Deepak;Lu, Xiongbin
通讯作者：
Lu, Xiongbin