A Role for TLR2 in Regulating Immune Surveillance in Pancreatic Ductal Adenocarcinoma

TLR2 在调节胰腺导管腺癌免疫监视中的作用

• 批准号: 10668252
• 负责人: Jacqueline Plesset
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668252
• 关键词: Affect; Amyloid; Apoptosis; Biology; Bone Marrow; Bone Marrow Cell Transplantation; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Death; Cell physiology; Cells; Cessation of life; Communication; Complement; Cytometry; Data; Development; Disease; Educational process of instructing; Endothelial Cells; Environment; Epithelial Cells; Flow Cytometry; Genetic; Harvest; Hematopoietic; Hepatocyte; Immune; Immune Evasion; Immunologic Surveillance; Immunologics; Immunotherapy; Implant; Infiltration; Injections; Institution; Knock-out; Knockout Mice; Knowledge; Kupffer Cells; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Mentorship; Metastatic Neoplasm to the Liver; Monitor; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Organ; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Productivity; Proteins; Publishing; Research; Resistance; Role; Serum; Serum amyloid A protein; Signal Pathway; Signal Transduction; Solid; Survival Rate; T cell infiltration; T cell regulation; T-Lymphocyte; TLR2 gene; Testing; Time; Training; Tumor Biology; Tumor Burden; Wild Type Mouse; Work; cell type; chimeric antigen receptor T cells; design; effector T cell; immune resistance; immunoregulation; improved; ineffective therapies; intravenous injection; liver function; liver inflammation; mortality; mouse model; new therapeutic target; novel; novel strategies; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; receptor; reconstitution; trafficking; tumor; tumor immunology

ABSTRACT Immunotherapy has shown remarkable benefit for some patients with solid cancers. However, it has largely been ineffective for the treatment of pancreatic ductal adenocarcinoma (PDAC). Notably, cancers with liver metastasis often show decreased responsiveness to immunotherapy and PDAC commonly metastasizes to the liver. Our lab has previously shown that PDAC triggers liver inflammation during early disease pathogenesis that subsequently supports metastasis to the liver. However, it remains unclear how the liver might influence outcomes to immunotherapy. The liver is classically known as an immunoregulatory organ involved in regulating T cell tolerance. Preliminary data show that serum amyloid A (SAA) proteins released by the liver in the setting of PDAC development suppress T cell surveillance in mouse models of PDAC such that genetic deletion of SAA converts PDAC tumors from T cell “poor” to T cell “rich”. SAA are known to signal through toll-like receptor 2 (TLR2) and consistent with this, preliminary data also show that genetic deletion of TLR2 causes T cell infiltration into PDAC tumors even in the presence of high levels of SAA. This finding implicates the SAA/TLR2 signaling pathway as a determinant of T cell surveillance in PDAC. However, little is known about how TLR2 regulates T cells surveillance in cancer. It is the central hypothesis of this proposal that TLR2 signaling causes sequestration of tumor-specific effector T cells in the liver which then undergo apoptosis, thereby limiting productive T cell surveillance in PDAC. To test this hypothesis, in Aim One I will define cellular mechanisms by which TLR2 regulates T cell surveillance in PDAC. In Aim Two, I will determine the impact of TLR2 on tumor-specific T cell fate and the efficacy of T cell immunotherapy. Altogether, studies in this proposal will improve our understanding of the role of tumor-extrinsic features in regulating immune resistance in PDAC with the aim to identify novel strategies for improving the efficacy of immunotherapy. This project will be sponsored by an established mentor with expertise in cancer immunology and tumor biology. This sponsorship entails a strong commitment to mentorship at an institution with an exceptional environment for training in cancer immunology and tumor biology. The project also includes a rigorous graduate training plan to complement training in scientific research with didactics and training in scientific communication and teaching.

抽象的 免疫疗法对一些实体癌患者显示出显着的益处。然而，这在很大程度上已经 对治疗胰腺导管腺癌（PDAC）无效。值得注意的是，伴有肝转移的癌症 通常表现出对免疫治疗的反应性下降，并且 PDAC 通常转移至肝脏。我们的 实验室此前已表明，PDAC 在早期疾病发病机制中会引发肝脏炎症， 随后支持肝脏转移。然而，目前尚不清楚肝脏如何影响 免疫治疗的结果。肝脏通常被称为免疫调节器官，参与调节 T细胞耐受性。初步数据显示，肝脏在环境中释放血清淀粉样 A (SAA) 蛋白 PDAC 发育的抑制抑制 PDAC 小鼠模型中的 T 细胞监视，从而导致 SAA 基因缺失 将 PDAC 肿瘤从 T 细胞“贫乏”转变为 T 细胞“丰富”。 SAA 已知通过 Toll 样受体 2 发出信号 (TLR2) 与此相一致的是，初步数据也显示TLR2基因缺失导致T细胞浸润 即使存在高水平的 SAA，也会进入 PDAC 肿瘤。这一发现暗示 SAA/TLR2 信号传导 途径作为 PDAC 中 T 细胞监视的决定因素。然而，人们对 TLR2 如何调节 T 知之甚少。 癌症中的细胞监测。该提案的中心假设是 TLR2 信号传导导致 肿瘤特异性效应T细胞被隔离在肝脏中，然后发生凋亡，从而 限制 PDAC 中的生产性 T 细胞监视。为了检验这一假设，在《目标一》中我将定义细胞 TLR2 调节 PDAC 中 T 细胞监视的机制。在目标二中，我将确定以下因素的影响： TLR2 对肿瘤特异性 T 细胞命运和 T 细胞免疫治疗疗效的影响。总而言之，本提案中的研究 将提高我们对肿瘤外在特征在调节 PDAC 免疫抵抗中的作用的理解 目的是确定提高免疫疗法疗效的新策略。该项目将 由具有癌症免疫学和肿瘤生物学专业知识的知名导师赞助。本次赞助 需要在具有特殊癌症培训环境的机构中坚定地致力于指导 免疫学和肿瘤生物学。该项目还包括严格的研究生培养计划以补充 科学研究与教学培训以及科学传播和教学培训。