Targeting the liver for immunotherapy in pancreatic cancer

以肝脏为靶点进行胰腺癌免疫治疗

• 批准号: 10364836
• 负责人: Gregory L Beatty
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364836
• 关键词: Acute-Phase Proteins; Address; Amyloid; Antigens; Applications Grants; Biology; CD8B1 gene; Cancer Model; Cell physiology; Cellular biology; Clinical; Data; Dendritic Cells; Deposition; Development; Environment; Exposure to; Extracellular Matrix Proteins; Funding; Genetic; Grant; Hepatic Stellate Cell; Hepatocyte; Homeostasis; Immune Evasion; Immunobiology; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; Impairment; Infiltration; Interleukin-6; KPC model; KRASG12D; Knowledge; Kupffer Cells; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metastatic Neoplasm to the Liver; Modeling; Molecular; Mus; Myeloid Cells; Neutrophil Infiltration; Non-Malignant; Organ; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Play; Portal vein structure; Primary Neoplasm; Process; Proteins; Reproducibility; Resistance; Retrospective Studies; Role; STAT3 gene; Serum; Shapes; Signal Pathway; Soil; T-Lymphocyte; Therapeutic; Tumor Escape; Tumor-infiltrating immune cells; Variant; cancer cell; cancer immunotherapy; carcinogenesis; clinically relevant; design; effector T cell; human disease; human tissue; immune checkpoint blockade; immunogenicity; immunoreaction; immunoregulation; improved outcome; liver inflammation; macrophage; melanoma; mouse model; novel; novel strategies; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; peripheral tolerance; systemic inflammatory response; tool; trafficking; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary Immunotherapy has shown the capacity to improve outcomes for some patients across a wide-range of malignancies. However, many patients still do not achieve clinical benefit and in particular, patients with liver metastases demonstrate poor responsiveness to immunotherapy. Emerging evidence suggest a role for the liver in determining outcomes with cancer immunotherapy. To this end, the liver is a critical determinant of immune regulation and plays a central role in T cell peripheral tolerance. Yet, how the liver may regulate immunotherapy efficacy is unclear. This represents a significant gap in our knowledge that has strong translational implications. In gastrointestinal malignancies, the liver may be continuously exposed to malignant cells as well as soluble factors and antigens released by primary tumors. We hypothesize that this connection between the gut and liver may have significant implications on T cell immunosurveillance in cancer. In support of this hypothesis, we have found that primary tumors release soluble factors that activate hepatocytes in the liver. This process can begin during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase reactants which act to orchestrate an immunological niche environment in the liver that is underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. In the setting of hepatocyte activation, primary tumor development, occurring in the pancreas, demonstrates poor T cell infiltration. However, genetic blockade of hepatocyte activation converts a T cell “cold” tumor into a “hot” tumor. This finding underscores the importance of the liver in regulating T cell immunosurveillance in cancer. Our priority is to decipher mechanisms by which the liver regulates T cell immunosurveillance in cancer and to understand its implications in regulating the efficacy of cancer immunotherapy. Therefore, in Aim 1, we will define mechanisms by which hepatocytes direct tumor immune evasion with a focus on signaling pathways regulated by hepatocytes and their impact on T cell priming and trafficking. In Aim 2, we will investigate the impact of hepatocyte activation on the immunobiology of PDAC and the efficacy of cancer immunotherapy. Together, these complementary aims will inform the development of novel treatment paradigms designed to curtail the immunosuppressive effects of liver inflammation as a strategy to broaden the efficacy of cancer immunotherapy.

项目摘要 免疫疗法表明能够改善某些患者的结局 恶性。但是，许多患者仍然无法获得临床益处，尤其是肝脏患者 转移表现出对免疫疗法的反应不佳。新兴证据表明肝脏的作用 在确定癌症免疫疗法的结果时。为此，肝脏是免疫疗法的关键决定剂 调节并在T细胞外周耐受性中起核心作用。然而，肝脏如何调节免疫疗法 效率尚不清楚。这在我们的知识上代表了具有强烈翻译意义的显着差距。 在胃肠道恶性肿瘤中，肝脏可以连续暴露于恶性细胞以及可溶性 原发性肿瘤释放的因素和抗原。我们假设肠道和肝脏之间的这种联系 可能对癌症中T细胞免疫监视具有显着影响。为了支持这一假设，我们有 发现原发性肿瘤释放激活肝细胞的固体因子。这个过程可以开始 在癌症发展的最早阶段。活化的肝细胞通过释放急性相反应 反应物在肝脏中策划免疫利基环境的反应物。 中性粒细胞和髓样细胞的募集以及细胞外基质蛋白的沉积。在 发生在胰腺中的肝细胞激活，原发性肿瘤的发育，表现出较差的T细胞 浸润。然而，肝细胞激活的遗传阻断将T细胞“冷”肿瘤转化为“热”肿瘤。 这一发现强调了生活在调节癌症中T细胞免疫监视的重要性。我们的优先事项 是解解肝脏调节癌症中T细胞免疫监视并了解的机制 它在确定癌症免疫疗法的效率方面的意义。因此，在AIM 1中，我们将定义 肝细胞直接肿瘤免疫避免的机制，重点是调节信号通路 通过肝细胞及其对T细胞启动和贩运的影响。在AIM 2中，我们将调查 肝细胞激活PDAC的免疫生物学和癌症免疫疗法的效率。在一起，这些 完成的目标将为旨在减少限制的新型治疗范式的发展提供信息 肝感染的免疫抑制作用是扩大癌症免疫疗法有效性的策略。