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 免疫疗法对某些固体癌症患者显示出显着的好处。但是，这主要是 无效治疗胰腺导管腺癌（PDAC）。值得注意的是，患有肝转移的癌症 通常显示对免疫疗法的反应性降低，而PDAC通常会转移到肝脏。我们的 LAB先前已经表明，PDAC在早期疾病发病机理中触发肝脏注射， 随后支持转移到肝脏。但是，尚不清楚肝脏如何影响 免疫疗法的结果。肝脏通常被称为与调节有关的免疫调节器官 T细胞耐受性。初步数据表明，肝脏在环境中释放的血清淀粉样蛋白A（SAA）蛋白 PDAC发育的抑制PDAC小鼠模型中T细胞监测，从而使SAA的遗传缺失 将PDAC肿瘤从T细胞“差”转换为T细胞“富含”。已知SAA通过T​​oll样接收器2发出信号2 （TLR2）并与此一致，初步数据还表明，TLR2的遗传缺失会导致T细胞浸润 即使存在高水平的SAA，也进入PDAC肿瘤。这一发现暗示了SAA/TLR2信号传导 途径是PDAC中T细胞监测的确定剂。但是，关于TLR2如何调节T的知之甚少 细胞监测癌症。这是该提议的中心假设，即TLR2信号引起 肝脏中肿瘤特异性效应T细胞的隔离，然后发生凋亡，从而 限制PDAC中的生产性T细胞监测。为了检验这一假设，在目标中，我将定义细胞 TLR2调节PDAC中T细胞监测的机制。在目标两个中，我将确定 TLR2在肿瘤特异性T细胞命运和T细胞免疫疗法的效率上。总共研究该提议 将提高我们对肿瘤 - 超支特征在控制PDAC中的免疫耐药性中的作用的理解 目的是确定提高免疫疗法效率的新型策略。这个项目将是 由既定的心理知识在癌症免疫学和肿瘤生物学方面的专业知识赞助。这个赞助 在具有癌症培训的特殊环境的机构中，对在机构进行训练的坚定承诺 免疫学和肿瘤生物学。该项目还包括一个严格的研究生培训计划 科学研究的培训和科学沟通和教学的教学和培训。