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

项目总结/摘要 胰腺导管腺癌（PDAC）是一种破坏性的恶性肿瘤，其特征是纤维化和 免疫抑制肿瘤微环境。采取创新办法，克服缺乏有效的 迫切需要PDAC中免疫应答。虽然治疗性感染的概念，使用 细菌作为免疫疗法，已经存在了世纪，最近的进展，我们的理解， 细菌与免疫细胞的相互作用以及与癌症相关的分子途径表明， 利用PDAC中天然细菌免疫调节特性的机会。我们已经开发 初步数据表明，A组链球菌（GAS）的注射激活抗肿瘤免疫 导致小鼠胰腺癌中的显著肿瘤消退。我们发现了一种细胞外 GAS上的一种蛋白Scl 1，可选择性结合胰腺肿瘤中的癌胚纤维连接蛋白（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Scl 1/cFN相互作用可能被利用作为 在直接注射到肿瘤中后，PDAC治疗的脱靶效应的限制机制。另外我们 已经发现GAS上的Scl 1阻断癌症促进中性粒细胞胞外陷阱（NETs）。自NET 负责促进PDAC中的肿瘤生长、转移性疾病和免疫抑制，这使得 利用GAS-Scl 1改变癌症发病机制和抗肿瘤免疫的巨大意义。肿瘤 在肿瘤内注射3种独特的GAS菌株后的生长和存活将在小鼠中进行评估 原位的、转移的和转基因的PDAC。肿瘤内GAS微集落的形成和结构 将通过双光子显微镜成像。GAS注射后的循环和肿瘤内NET将 测量并产生稳健的免疫谱以鉴定免疫调节作用。建议授出 将破译驱动GAS-Scl 1刺激抗肿瘤免疫能力的新机制， 阐明利用GAS-Scl 1的非感染性策略在未来治疗 PDAC的。

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 .