Targeting the liver for immunotherapy in pancreatic cancer

以肝脏为靶点进行胰腺癌免疫治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要免疫疗法已显示出能够改善某些患者的多种治疗结果然而，许多患者仍然没有获得临床获益，特别是肝癌患者。新的证据表明转移瘤对免疫治疗的反应较差。为此，肝脏是免疫的关键决定因素。然而，肝脏如何调节免疫治疗。功效尚不清楚。这代表了我们知识上的重大差距，具有很强的转化意义。在胃肠道恶性肿瘤中，肝脏可能持续暴露于恶性细胞以及可溶性细胞中。我们探索了肠道和肝脏之间的这种联系。可能对癌症中的 T 细胞免疫监视具有重大影响为了支持这一假设，我们有发现原发性肿瘤释放可溶性因子，激活肝脏中的肝细胞，这一过程就可以开始。在癌症发展的最早阶段，激活的肝细胞通过释放急性期做出反应。反应物在肝脏中协调免疫生态位环境，该环境由中性粒细胞和骨髓细胞的募集以及细胞外基质蛋白的沉积。发生在胰腺中的肝细胞活化、原发性肿瘤发展表明 T 细胞较差然而，肝细胞激活的基因阻断会将 T 细胞“冷”肿瘤转化为“热”肿瘤。这一发现强调了肝脏在调节癌症 T 细胞免疫监视方面的重要性。旨在破译肝脏在癌症中调节 T 细胞免疫监视的机制并了解它对调节癌症免疫疗法疗效的影响因此，在目标 1 中，我们将定义。肝细胞引导肿瘤免疫逃避的机制，重点关注信号通路的调节在目标 2 中，我们将研究肝细胞的影响及其对 T 细胞启动和运输的影响。肝细胞激活对 PDAC 免疫生物学和癌症免疫治疗功效的影响。互补的目标将为开发新的治疗范式提供信息，旨在减少肝脏炎症的免疫抑制作用作为扩大癌症免疫治疗疗效的策略。