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Targeting Small Nucleolar RNA Augments Immunotherapeutic Efficacy

靶向小核仁 RNA 增强免疫治疗功效

基本信息

批准号：
10443334
负责人：
Chunru Lin
金额：
$ 48.36万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443334
关键词：
Address Adipocytes Adipose tissue Antisense Oligonucleotides Attenuated Automobile Driving Binding Biological Blood Body mass index Breast Cancer Patient CD8-Positive T-Lymphocytes CD8B1 gene Cells Chromatin Clinical Data Development Down-Regulation Drug Kinetics Energy Metabolism Essential Genes Event Exhibits Foundations GTP-Binding Protein alpha Subunits, Gs Gene Targeting Genes Genetic Genetic Transcription Goals High Fat Diet Immunotherapeutic agent Immunotherapy Impairment Infiltration Interleukin-15 Knock-in Knock-in Mouse Knowledge Leukocytes Lipolysis Malignant Neoplasms Mammary Neoplasms Mammary gland Mechanics Mediating Molecular Monoacylglycerol Lipases Mouse Mammary Tumor Virus Mouse Strains Mus Natural Killer Cell toxicity Natural Killer Cells Normal tissue morphology Obese Mice Obesity Outcome PD-1/PD-L1 PD-L1 blockade Pathway interactions Phosphorylation Process Resistance Risk Factors Role Sampling Serum Signal Pathway Signal Transduction Small Nucleolar RNA Stat5 protein Therapeutic Toxic effect Tumor Immunity Tumor-infiltrating immune cells Underweight Untranslated RNA Up-Regulation Variant base bone breast cancer progression cancer initiation cancer type computational pipelines cytotoxic diet-induced obesity effectiveness evaluation genetic variant glucose metabolism immune checkpoint blockers immune resistance improved in vivo infiltrating duct carcinoma interleukin-15 receptor knock-down lipid biosynthesis locked nucleic acid malignant breast neoplasm next generation obese patients survival outcome targeted treatment therapeutic target treatment strategy triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

Project Summary Despite the establishment of obesity as a risk factor in the development of a multitude of cancer types including breast cancer, there is still a significant insufficiency of genetic evidence for implicating obesity in the initiation and progression of breast cancer development. While immunotherapeutic approaches such as the PD-1/PD-L1 blockade have shown promise in treating breast cancer, obesity causes substantial impairment of anti-tumor immunity. A significant challenge in the development of effective immunotherapeutic strategies for obesity- associated breast cancer lies in the characterization of the bone fide target genes that drive obesity-associated immune resistance. The emergence of noncoding RNAs as important biological molecules has provided the foundation for the development of next-generation treatment strategies. Our preliminary data demonstrated that a small nucleolar RNA (snoRNA), SNORD46, is upregulated in breast cancer and negatively correlated with the infiltration of cytotoxic leukocytes. We also indicated that obesity is associated with a chromatin variant of SNORD46. We collected genetic evidence indicating that the expression of SNORD46 leads to obesity and mammary gland tumors which are resistant to immunotherapy. Therefore, the goal of this proposal is to comprehensively characterize and implicate SNORD46 as a driver of obesity-associated breast cancer and demonstrate that targeting snoRNAs effectively improves the expansion and activation of CD8+ T-cells and NK cells and sensitizes obesity-associate breast cancer in immunotherapy. We will address our central hypothesis that snoRNAs act as essential gene targets that promote obesity and obesity-associated breast cancer initiation and immune resistance, which could be attenuated in vivo by an anti- sense oligonucleotide-based targeted therapy. In Specific Aim 1, we will define the molecular mechanism of SNORD46 inhibited, IL-15-dependent non-classic pathway in adipocytes, and IL-15-dependent expression of stimulatory checkpoints in CD8+ T cell and NK cells. In Specific Aim 2, we will ascertain the functional importance of snoRNAs in obesity-associated tumorigenesis and immune resistance using high-fat diet-induced obese mice and Snord46 mut/mut knockin obese mice. The proposed study will provide initial genetic evidence for defining the crucial role of adipocyte-expressed snoRNAs in promoting obesity and obesity-associated breast cancer. Mechanistically, we will elucidate the molecular mechanisms of the SNORD46-leukocyte interactions that drive obesity-associated breast cancer resistance to immunotherapy. Clinically, the proposed studies will delineate that targeting snoRNAs using locked nucleic acids (LNAs) effectively improves the proliferation/activation of CD8+ T-cells and NK cells in vivo, sensitizing obesity-associated breast cancer to immune checkpoint blockers.

项目概要尽管肥胖已被确定为多种癌症类型发展的危险因素，包括乳腺癌，目前仍缺乏足够的遗传证据表明肥胖与乳腺癌的发生有关和乳腺癌发展的进展。虽然PD-1/PD-L1等免疫治疗方法封锁在治疗乳腺癌方面显示出希望，肥胖导致抗肿瘤能力显着受损免疫。开发有效的肥胖免疫治疗策略的一个重大挑战是与乳腺癌相关的因素在于驱动肥胖相关的真正靶基因的特征免疫抵抗力。非编码RNA作为重要的生物分子的出现提供了为制定下一代治疗策略奠定了基础。我们的初步数据表明一种小核仁 RNA (snoRNA) SNORD46 在乳腺癌中表达上调，并与细胞毒性白细胞浸润。我们还表明肥胖与染色质变异有关斯诺德46。我们收集的遗传证据表明 SNORD46 的表达会导致肥胖和对免疫治疗有抵抗力的乳腺肿瘤。因此，本提案的目标是全面描述并暗示 SNORD46 是肥胖相关乳腺癌的驱动因素，证明靶向 snoRNA 可有效改善 CD8+ T 细胞和 NK 的扩增和激活细胞并使免疫治疗中与肥胖相关的乳腺癌变得敏感。我们将解决我们的中心假设，即 snoRNA 作为促进肥胖和肥胖的重要基因靶标。肥胖相关的乳腺癌发生和免疫抵抗，可以通过抗- 基于有义寡核苷酸的靶向治疗。在具体目标1中，我们将定义其分子机制 SNORD46 抑制脂肪细胞中 IL-15 依赖性非经典途径以及 IL-15 依赖性表达 CD8+ T 细胞和 NK 细胞中的刺激检查点。在具体目标 2 中，我们将确定功能重要性使用高脂饮食诱导的肥胖小鼠研究 snoRNA 在肥胖相关肿瘤发生和免疫抵抗中的作用和 Snord46 mut/mut 敲入肥胖小鼠。拟议的研究将为定义脂肪细胞表达的关键作用提供初步的遗传证据。 snoRNA 促进肥胖和肥胖相关乳腺癌。从机制上讲，我们将阐明 SNORD46-白细胞相互作用驱动肥胖相关乳腺癌的分子机制对免疫治疗的抵抗。在临床上，拟议的研究将描述使用锁定的 snoRNA 靶向核酸（LNA）有效改善体内CD8+ T细胞和NK细胞的增殖/活化，使肥胖相关乳腺癌对免疫检查点阻断剂敏感。