Mechanisms of anti-tumor activity of group A Streptococcus in pancreatic adenocarcinoma

A族链球菌抗胰腺癌的作用机制

• 批准号: 10662559
• 负责人: BRIAN A BOONE
• 金额: $ 20.89万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662559
• 关键词: Adult; Automobile Driving; Bacteria; Binding; Cells; Circulation; Collagen; Data; Disease; Dose; Engineering; Extracellular Protein; Future; Grant; Group Structure; Helper-Inducer T-Lymphocyte; Image; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Stimulation; Immunology; Immunosuppression; Immunotherapy; Infection; Infiltration; Inflammatory Response; Injections; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Microbiology; Modeling; Molecular; Monitor; Mus; Mutation; Myeloid-derived suppressor cells; Nature; Neoplasm Metastasis; Outcome; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathology; Pathway interactions; Patient-Focused Outcomes; Play; Property; Proteins; Resolution; Role; Scientist; Skin; Streptococcus; Streptococcus pyogenes; Surface; TP53 gene; Therapeutic; Therapeutic Effect; Time; Tissues; Transgenic Organisms; Treatment Efficacy; Tumor Immunity; Tumor Promotion; Wild Type Mouse; anti-cancer; cytokine; cytotoxic; experimental study; extracellular; fighting; granulocyte; high reward; high risk; immune activation; immunoregulation; improved; inflammatory modulation; innovation; insight; mutant; neoantigens; neutrophil; novel; oncofetal fibronectin; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pre-clinical; prevent; success; targeted treatment; therapy resistant; translational study; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; two photon microscopy; ultrasound

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by a fibrotic and immunosuppressive tumor microenvironment. Innovative approaches to overcome the lack of an effective immune response in PDAC are desperately needed. Although the concept of therapeutic infection, using bacteria as immunotherapy, has been around for over a century, recent advances in our understanding of bacterial interaction with immune cells and molecular pathways with relevance in cancer suggest new opportunities to harness natural bacterial immunomodulatory properties in PDAC. We have developed preliminary data demonstrating that injection of Group A Streptococcus (GAS) activates anti-tumor immunity resulting in profound tumor regression in murine pancreatic cancer. We have identified an extracellular protein, Scl1, on GAS, which selectively binds oncofetal fibronectin (cFn) in the pancreatic tumor microenvironment, suggesting the potential for bacterial localization to pancreatic tumors. Importantly, cFn is expressed in pancreatic tumors, but not healthy tissues, therefore Scl1/cFN interaction may be harnessed as a mechanism to limit off-target effects of PDAC treatment following direct injection into tumors. Additionally, we have discovered that Scl1 on GAS blocks cancer promoting neutrophil extracellular traps (NETs). Since NETs are responsible for promotion of tumor growth, metastatic disease and immunosuppression in PDAC, this has tremendous implications for utilizing GAS-Scl1 to alter cancer pathogenesis and anti-tumor immunity. Tumor growth and survival after intra-tumoral injection of 3 unique strains of GAS will be assessed in murine orthotopic, metastatic and transgenic PDAC. The formation and structure of GAS microcolonies within tumors will be imaged by two-photon microscopy. Circulating and intra-tumoral NETs after GAS injection will be measured and a robust immune profile generated to identify immunomodulatory effects. The proposed grant will decipher novel mechanisms driving the capability of GAS-Scl1 to stimulate anti-tumor immunity and elucidate the therapeutic potential of non-infectious strategies harnessing GAS-Scl1 in a future treatment for PDAC .

项目概要/摘要 胰腺导管腺癌（PDAC）是一种破坏性恶性肿瘤，其特征是纤维化和 免疫抑制肿瘤微环境。创新方法，克服缺乏有效的 PDAC 中迫切需要免疫反应。尽管治疗性感染的概念，使用 细菌作为免疫疗法已经存在一个多世纪了，我们对细菌的理解的最新进展 细菌与免疫细胞的相互作用以及与癌症相关的分子途径提出了新的建议 利用 PDAC 天然细菌免疫调节特性的机会。我们开发了 初步数据表明注射 A 族链球菌 (GAS) 可激活抗肿瘤免疫 导致小鼠胰腺癌的肿瘤显着消退。我们已经鉴定出一种细胞外 GAS 上的蛋白质 Scl1，选择性结合胰腺肿瘤中的癌胎纤连蛋白 (cFn) 微环境，表明细菌定位于胰腺肿瘤的潜力。重要的是，cFn 是 在胰腺肿瘤中表达，但在健康组织中不表达，因此 Scl1/cFN 相互作用可以作为一种 限制直接注射到肿瘤后 PDAC 治疗脱靶效应的机制。此外，我们 研究人员发现 GAS 上的 Scl1 可以阻断促癌的中性粒细胞胞外陷阱 (NET)。自从NET 负责促进 PDAC 中的肿瘤生长、转移性疾病和免疫抑制，这 利用 GAS-Scl1 改变癌症发病机制和抗肿瘤免疫具有巨大意义。瘤 将评估小鼠肿瘤内注射 3 种独特的 GAS 菌株后的生长和存活率 原位、转移和转基因 PDAC。肿瘤内 GAS 微菌落的形成和结构 将通过双光子显微镜成像。 GAS 注射后的循环和肿瘤内 NET 将被 测量并生成强大的免疫特征来识别免疫调节作用。拟议拨款 将破译驱动 GAS-Scl1 刺激抗肿瘤免疫能力的新机制 阐明利用 GAS-Scl1 的非感染性策略在未来治疗中的治疗潜力 PDAC。