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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

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 .

项目总结/文摘