Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy

靶向 B7-H4 的翻译后修饰在癌发生和治疗中的作用

基本信息

批准号：
10523400
负责人：
Yong Wan
金额：
$ 51.82万
依托单位：
EMORY 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：
2021-11-09 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523400
关键词：
Breast Cancer Treatment Breast Cancer therapy Breast Carcinogenesis CD8-Positive T-Lymphocytes CD8B1 gene Cellular Stress Chemosensitization Complex Data Dendritic Cells Doxorubicin Enzymes Goals Heat-Shock Proteins 70 Heat-Shock Proteins 90 Immune checkpoint inhibitor Immunosuppression Immunotherapy Interferons Lead Mammary Neoplasms Mediating Modeling Molecular Neoplasm Metastasis Oncogenic Pathologic Pattern Phagocytosis Pharmaceutical Preparations Pharmacology Physiological Post-Translational Protein Processing Prognosis Protein Glycosylation Proteins Role Signal Transduction T cell response T-Lymphocyte Testing The Cancer Genome Atlas Therapeutic Tumor Escape Tumor Promotion Ubiquitination VTCN1 gene cancer type carcinogenesis chemotherapy clinical efficacy clinically relevant endoplasmic reticulum stress glycosylation glycosyltransferase immune checkpoint immunogenic cell death in vivo inhibitor malignant breast neoplasm mouse model neoplastic cell novel novel therapeutic intervention pre-clinical protein complex recruit response targeted cancer therapy triple-negative invasive breast carcinoma tumor tumor eradication tumor progression ubiquitin-protein ligase

项目摘要

Targeting post-translational modifications of B7-H4 in carcinogenesis and therapy The goal of this project is to determine the impact of interplay between glycosylation and ubiquitination of B7-H4 in breast carcinogenesis and anti-breast cancer therapy. B7-H4, also known as V-set domain containing T cell activation inhibitor 1 (VTCN1), acts as an immune checkpoint protein whose local abnormal accumulation is correlated with poor prognosis of various types of cancers including triple negative breast cancer (TNBC). While a current TCGA study suggests the critical role of B7-H4 in conferring tumor sensitivity to chemotherapy drugs and immune checkpoint inhibitors, how B7-H4 is regulated and how its deregulation contributes to breast carcinogenesis and tumor drug response remain unknown. Results from our recent purification of the B7-H4 protein complex revealed that 2 critical enzymes, AMFR and STT3 complex, tightly interact with and regulate B7-H7. While the E3 ubiquitin ligase AMFR catalyzes ubiquitination of B7-H4 followed by degradation, we observed that glycosylation of B7-H4 protein by the STT3 complex (a glycosyltransferase) results in the stabilization of B7-H4 and inhibition of doxorubicin-induced immunogenic cell death (ICD). Elevation of B7-H4 levels due to enhanced B7-H4 glycosylation counteracts B7-H4 ubiquitination, which in turn suppresses endoplasmic reticulum stress-mediated phagocytosis in response to chemotherapy drugs, a critical step in triggering mass tumor eradication by ICD. We further demonstrated that blockade of B7-H4 glycosylation by NGI-1, a novel protein glycosylation inhibitor, significantly enhances B7-H4 ubiquitination and subsequent degradation, resulting in promotion of tumor killing efficacy due to increased phagocytosis by dendritic cells and their capacity to elicit CD8+ interferon-γ-producing T cell responses. In this project, we plan to test the hypothesis that deregulation of B7-H4 by the crosstalk between glycosylation and ubiquitination promotes TNBC tumor evasion from chemotherapy and blockade of B7-H4 glycosylation by NGI-1 could be a new strategy for anti-TNBC treatment. We propose the following specific aims to pursue this goal: (1) to determine the mechanism by which interplay between glycosylation and ubiquitination regulates B7-H4-orchestrated phagocytosis; (2) to determine the physiological relevance of STT3-mediated glycosylation and AMFR-facilitated ubiquitination in B7-H4-mediated ICD in response to chemotherapy drugs; and (3) to determine the clinical relevance of blockade of B7-H4 glycosylation by NGI-1 in anti-TNBC treatment using various preclinical murine models.

靶向癌变和治疗中B7-H4的翻译后修饰该项目的目的是确定B7-H4糖基化和泛素化之间相互作用的影响在乳腺癌作用和抗胸腺癌治疗中。 B7-H4，也称为含T细胞的V-stet域激活抑制剂1（VTCN1）充当一种免疫粘点蛋白，其局部异常积累是与各种类型的癌症（包括三重阴性乳腺癌（TNBC））的预后不良相关。尽管当前的TCGA研究表明，B7-H4在肿瘤对化疗药物的敏感性中的关键作用和免疫粘点抑制剂，如何调节B7-H4以及其放松管制如何促进乳房癌变和肿瘤药物反应仍然未知。我们最近纯化B7-H4的结果蛋白质复合物显示2种关键酶，AMFR和STT3复合物，紧密相互作用并调节 B7-H7。 E3泛素连接酶AMFR催化B7-H4的泛素化，然后降解，我们观察到通过STT3复合物（糖基转移酶）对B7-H4蛋白的糖基化导致 B7-H4的稳定和阿霉素诱导的免疫原性死亡（ICD）的抑制作用。 B7-H4的升高由于增强的B7-H4糖基化的水平抵消B7-H4泛素化，从而抑制了B7-H4的泛素化响应化学疗法药物的内质网应激介导的吞噬作用，这是关键的一步通过ICD触发质量肿瘤辐射。我们进一步证明了通过 NGI-1是一种新型蛋白质糖基化抑制剂，显着增强了B7-H4泛素化和随后的泛素化降解，导致促进树突状细胞吞噬作用增加引起的肿瘤杀伤效率它们引起CD8+干扰素-γ产生的T细胞反应的能力。在这个项目中，我们计划测试假设通过糖基化和泛素化之间的串扰对B7-H4进行管制会促进 TNBC肿瘤从化学疗法和通过NGI-1封闭B7-H4糖基化的封锁可能是一种新策略用于抗TNBC治疗。我们提出以下具体目的来追求这一目标：（1）确定糖基化和泛素化之间相互作用的机制调节B7-h4原处理吞噬作用；（2）确定STT3介导的糖基化和AMFR-促溶质的物理相关性 B7-H4介导的ICD的泛素化响应化学疗法药物；（3）确定临床 NGI-1在抗TNBC处理中使用各种临床前鼠在抗TNBC处理中通过NGI-1的相关性型号。