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

• 批准号: 10361572
• 负责人: Yong Wan
• 金额: --
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-09 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361572
• 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; Interferon Type II; Lead; Mammary Neoplasms; Mediating; Modeling; Molecular; Neoplasm Metastasis; Oncogenic; Pathologic; Pattern; Phagocytosis; Pharmaceutical Preparations; 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; pharmacologic; pre-clinical; protein complex; recruit; response; targeted cancer therapy; triple-negative invasive breast carcinoma; tumor; tumor eradication; tumor progression; ubiquitin-protein ligase

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 B7-H4 的翻译后修饰在癌发生和治疗中的作用 该项目的目标是确定 B7-H4 糖基化和泛素化之间相互作用的影响 B7-H4，也称为含有 V-set 结构域的 T 细胞，用于乳腺癌发生和抗乳腺癌治疗。 激活抑制剂 1 (VTCN1)，作为免疫检查点蛋白，其局部异常积累 与包括三阴性乳腺癌（TNBC）在内的多种癌症的不良预后相关。 目前的 TCGA 研究表明 B7-H4 在赋予肿瘤对化疗药物敏感性方面发挥着关键作用 和免疫检查点抑制剂，B7-H4 的调节方式以及其放松管制对乳腺的影响 我们最近纯化 B7-H4 的致癌作用和肿瘤药物反应的结果仍然未知。 蛋白质复合物揭示了 2 种关键酶 AMFR 和 STT3 复合物紧密相互作用并调节 B7-H7。虽然 E3 泛素连接酶 AMFR 催化 B7-H4 泛素化，然后降解，但我们 观察到 B7-H4 蛋白被 STT3 复合物（一种糖基转移酶）糖基化导致 稳定 B7-H4 并抑制阿霉素诱导的免疫原性细胞死亡 (ICD)。 由于 B7-H4 糖基化增强而导致的水平升高抵消了 B7-H4 泛素化，从而抑制 内质网应激介导的吞噬作用对化疗药物的反应，这是细胞凋亡的关键一步 我们进一步证明了 ICD 可以阻断 B7-H4 糖基化。 NGI-1 是一种新型蛋白质糖基化抑制剂，可显着增强 B7-H4 泛素化并随后 降解，由于树突状细胞的吞噬作用增加而促进肿瘤杀伤功效， 在这个项目中，我们计划测试它们引发产生 CD8+ 干扰素 γ 的 T 细胞反应的能力。 糖基化和泛素化之间的串扰导致 B7-H4 失调的假设促进 TNBC 肿瘤逃避化疗和 NGI-1 阻断 B7-H4 糖基化可能是一种新策略 对于抗TNBC治疗，我们提出以下具体目标来实现这一目标：（1）确定治疗目标。 糖基化和泛素化之间的相互作用调节 B7-H4 协调的机制 吞噬作用；(2) 确定 STT3 介导的糖基化和 AMFR 促进的生理相关性 B7-H4 介导的 ICD 响应化疗药物的泛素化；以及 (3) 确定临床效果； NGI-1 阻断 B7-H4 糖基化在使用各种临床前小鼠的抗 TNBC 治疗中的相关性 模型。