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.

摘要 免疫疗法已显示出对一些实体癌患者的显著益处。然而，这在很大程度上是 对胰腺导管腺癌(PDAC)治疗无效。值得注意的是，有肝转移的癌症 通常表现为对免疫治疗的反应性降低，PDAC通常转移到肝脏。我们的 实验室先前已经表明，PDAC在早期疾病发病机制中触发肝脏炎症 随后支持肝脏转移。然而，目前尚不清楚肝脏可能会如何影响 免疫治疗的结果。传统上，肝脏是一种免疫调节器官，参与调节 T细胞耐受性。初步数据显示，血清淀粉样蛋白A(SAA)由肝脏在设定的时间内释放 PDAC的发育抑制了PDAC小鼠模型中的T细胞监视，从而导致SAA的基因缺失 将PDAC肿瘤从T细胞“穷”转变为T细胞“富”。已知SAA通过Toll样受体2发出信号 (TLR2)与此一致，初步数据也表明TLR2的基因缺失会导致T细胞渗透 即使在高水平的SAA存在的情况下，也可以将其转化为PDAC肿瘤。这一发现涉及SAA/TLR2信号 通路作为PDAC中T细胞监视的决定因素。然而，人们对TLR2如何调节T却知之甚少 癌症中的细胞监测。这是这个建议的中心假设，TLR2信号导致 肿瘤特异性效应T细胞在肝脏中的隔离，然后经历细胞凋亡，从而 限制PDAC中生产性T细胞的监测。为了验证这一假设，在目标一中，我将定义细胞 TLR2调节PDAC中T细胞监视的机制在第二个目标中，我将确定 TLR2对肿瘤特异性T细胞去向及T细胞免疫治疗效果的影响总之，这项提案中的研究 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。这个项目将是 由一位在癌症免疫学和肿瘤生物学方面具有专业知识的知名导师赞助。这项赞助 需要坚定地承诺在一所拥有特殊癌症培训环境的机构进行指导 免疫学和肿瘤生物学。该项目还包括一项严格的研究生培训计划，以补充 教学科研培训和科学交流与教学培训。