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

基本信息

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
项目类别：
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

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

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项目摘要

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 .

项目摘要/摘要胰腺导管腺癌（PDAC）是一种毁灭性的恶性肿瘤，其特征是纤维化和免疫抑制肿瘤微环境。创新的方法来克服缺乏有效的迫切需要PDAC中的免疫反应。虽然是治疗感染的概念，但细菌作为免疫疗法，已经存在了一个多世纪，我们对与免疫细胞和与癌症相关的分子途径的细菌相互作用表明了新的利用PDAC中天然细菌免疫调节特性的机会。我们已经发展了初步数据表明，注射A组链球菌（气）激活抗肿瘤免疫力导致鼠胰腺癌的深度肿瘤消退。我们已经确定了细胞外蛋白质SCL1在气体上，在胰腺肿瘤中有选择地结合肩fet骨纤连蛋白（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不健康的组织，因此SCL1/CFN相互作用可能被视为直接注射到肿瘤后，限制PDAC治疗的脱靶作用的机制。另外，我们已经发现，在气体块上SCL1促进中性粒细胞外陷阱（NETS）。由于网负责促进PDAC中肿瘤生长，转移性疾病和免疫抑制，这有利用GAS-SCL1改变癌症发病机理和抗肿瘤免疫的巨大含义。瘤在鼠类内注射3种独特的气体菌株后的生长和存活率将在鼠中评估原位，转移和转基因PDAC。肿瘤内气体菌落的形成和结构将通过两光子显微镜成像。注射气体后循环和肿瘤内网将是测量并产生了可靠的免疫特征，以鉴定免疫调节作用。拟议的赠款将破译新的机制，以驱动气体-SCL1刺激抗肿瘤免疫力的能力和阐明非感染策略在未来治疗中利用GAS-SCL1的治疗潜力 PDAC。