Wnt3a is a central regulator for P. gingivalis-mediated expression of PD-L1 and suppression of CD8+ T cell activity

Wnt3a 是牙龈卟啉单胞菌介导的 PD-L1 表达和 CD8 T 细胞活性抑制的中心调节因子

• 批准号: 10592576
• 负责人: Huizhi Wang
• 金额: $ 23.29万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592576
• 关键词: Allogenic; Antigens; Autocrine Communication; Bone Marrow; CD8-Positive T-Lymphocytes; Cancer Control; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Cytotoxic T-Lymphocytes; DNA Binding; Data; Dendritic Cells; Development; Enhancers; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Family; Genes; Genetic Transcription; Goals; Granzyme; Immune; Immune signaling; Immune system; Immunomodulators; Immunotherapy; Impairment; Infection; Inflammation; Innate Immune Response; Interferons; Intervention; Invaded; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of esophagus; Maps; Mediating; Molecular; Mutate; Myelogenous; Nuclear Translocation; Oral cavity; Organism; Outcome; PD-1 blockade; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phosphorylation; Porphyromonas gingivalis; Proteins; Publications; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; T cell response; Testing; Tissue Preservation; Tissues; Work; cancer cell; cell growth; chronic infection; cytotoxicity; disorder control; exhaust; experimental study; healing; heart preservation; high reward; immune system function; immunoregulation; in vivo; innovation; interest; neoplastic cell; novel; organ growth; perforin; programmed cell death protein 1; programs; receptor; response; success; tumor; tumor progression; upstream kinase

Abstract Blockade of program death ligand-1 (PD-L1) is demonstrating remarkable clinical outcomes for patients with cancer or chronic infection through reinvigorating exhausted CD8+ T cell responses. However, only a small portion of patients can respond well to this treatment, indicating a dire need for an in-depth understanding of the function and regulatory mechanisms of PD-L1. Recent breakthrough findings revealed that expression of PD-L1 on dendritic cells (DCs) is critical for the efficacy of PD-L1/PD-1 blockade immunotherapy. Porphyromonas gingivalis (Pg) is a causative agent of chronic periodontal inflammation and tissue damages. Infection with Pg was reported to aggravate cancer progression and promote PD-L1 expression in tumor cells. However, if and how Pg infection promotes expression of PD-L1 on DCs and its possible effect on CD8+ T cell activity remain entirely unknown. Thus, it is tempting to identify novel immune signaling modulators that can regulate expression of PD-L1 and impact cytotoxic T cell activity, with a long-term goal of restoring the immune system function in surveillance and elimination of invaded organisms and cancer cells. Our recent studies demonstrated that Pg infection robustly increases expression of Wnt (Winglesss and Int-1) 3a in innate immune cells and Wnt3a negatively regulates the intensity of innate immune responses. Our preliminary data suggest that Pg infection (i) significantly enhances PD-L1 expression on BMDCs and impairs cytotoxicity of allogenic antigen-specific CD8+ T cells; (ii) remarkably enhances expression of Wnt3a, and inhibition of Wnt3a reduces expression of PD-L1 on BMDCs; and (iii) leads to an increase of Yes-associated protein 1(YAP) and WW- domain-containing transcription regulator-1(TAZ) expression but a decrease of an upstream kinase phosphorylation in DCs. Since YAP/TAZ was shown to associate with PD-L1 expression and interact with Wnt3a signaling in other contexts, we thus hypothesize that Wnt3a is a critical immunomodulator that promotes PD-L1 expression and suppresses CD8+ T cell activity upon stimulation with Pg by regulating activation of YAP/TAZ signaling and its downstream transcriptional enhancer factor (TEA)-domain family of DNA- binding factor 1 (TEAD1). We will demonstrate this hypothesis with two specific aims: (1): Establish the role of Wnt3a as an endogenous regulator of the Pg-induced PD-L1 and impairment of CD8+ T cell activity; (2) Establish if Wnt3a promotes Pg-induced PD-L1 expression and impairment of CD8+ T cell activity via modifying the activity of YAP/TAZ and its downstream TEAD1. Successful completion of this project will (i) maps out a novel and potentially critical signaling pathway (Wnt3a-YAP/TAZ-TEAD1) and identifies more interventional targets in PD-L1 expression; and (ii) greatly aids in understanding the regulatory mechanism that Pg infection impairs CD8+ T cell cytotoxicity, which will pave the way for the development of innovative immunoregulatory therapies for the control of cancer and chronic infections via manipulating activity of Wnt3- YAP/TAZ that should have relevance well beyond oral cavity.

抽象的 阻断程序死亡配体 1 (PD-L1) 为患者带来了显着的临床效果 通过重振耗尽的 CD8+ T 细胞反应来对抗癌症或慢性感染。然而，只有一小部分 部分患者对这种治疗反应良好，这表明迫切需要深入了解 PD-L1的功能和调控机制。最近的突破性发现表明 PD-L1 的表达 树突状细胞 (DC) 的作用对于 PD-L1/PD-1 阻断免疫疗法的疗效至关重要。卟啉单胞菌属 牙龈炎（Pg）是慢性牙周炎症和组织损伤的病原体。 PG感染 据报道，它会加剧癌症进展并促进肿瘤细胞中 PD-L1 的表达。然而，如果并且 Pg感染如何促进DC上PD-L1的表达及其对CD8+ T细胞活性的可能影响 仍然完全未知。因此，寻找新型免疫信号调节剂是很有吸引力的。 调节 PD-L1 的表达并影响细胞毒性 T 细胞活性，长期目标是恢复免疫 系统功能监视和消除入侵的生物体和癌细胞。我们最近的研究 证明 Pg 感染可显着增加先天免疫中 Wnt（Winglesss 和 Int-1）3a 的表达 细胞和 Wnt3a 负向调节先天免疫反应的强度。我们的初步数据表明 Pg 感染 (i) 显着增强 BMDC 上的 PD-L1 表达并削弱同种异体的细胞毒性 抗原特异性 CD8+ T 细胞； (ii) 显着增强 Wnt3a 的表达，抑制 Wnt3a 则降低 PD-L1在BMDC上的表达； (iii) 导致 Yes 相关蛋白 1 (YAP) 和 WW- 的增加 包含转录调节因子 1 (TAZ) 的结构域表达，但上游激酶减少 DC 中的磷酸化。由于 YAP/TAZ 被证明与 PD-L1 表达相关并与 Wnt3a 相互作用 因此，我们假设 Wnt3a 是一种关键的免疫调节剂，可促进 Pg 刺激后通过调节激活来抑制 PD-L1 表达并抑制 CD8+ T 细胞活性 YAP/TAZ 信号传导及其下游转录增强因子 (TEA)-DNA 结构域家族 结合因子 1 (TEAD1)。我们将通过两个具体目标来论证这一假设：(1)：建立角色 Wnt3a 作为 Pg 诱导的 PD-L1 的内源性调节剂并损害 CD8+ T 细胞活性； (2) 确定 Wnt3a 是否促进 Pg 诱导的 PD-L1 表达并损害 CD8+ T 细胞活性 改变 YAP/TAZ 及其下游 TEAD1 的活性。该项目的成功完成将 (i) 绘制出一条新颖且潜在关键的信号通路 (Wnt3a-YAP/TAZ-TEAD1) 并确定更多 PD-L1表达的干预靶点； (ii) 极大地帮助理解监管机制 Pg感染会损害CD8+ T细胞的细胞毒性，这将为创新药物的开发铺平道路 通过操纵 Wnt3- 活性来控制癌症和慢性感染的免疫调节疗法 YAP/TAZ 的相关性应该远远超出口腔范围。