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.

项目摘要免疫疗法表明，对于一些大范围的某些患者，可以改善一些患者的预后但是，许多患者仍然没有临床益处，尤其是肝脏转移表现出对免疫疗法的反应不良。在确定癌症的结果时，肝脏是免疫的关键调节和在T细胞外围起着核心作用，肝脏如何调节免疫疗法功效不清楚。在胃静脉内恶性肿瘤中，肝脏可能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。可能对癌症中的T细胞含量有显着影响。发现原发性肿瘤释放了肝脏中的肝细胞。在癌症发展的阶段在肝脏中策划免疫学生态位环境的反应物，由您支撑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。发生在胰腺中的肝细胞激活，原发性肿瘤发育，表明毛孔很差。然而，浸润。这一发现降低了肝脏在调节癌症中的T细胞免疫监视方面的重要性。是破译机制，肝脏将T细胞免疫监视并理解它在调节癌症免疫疗法的功效中的意义。肝细胞直接肿瘤免疫的机制，重点是信号通路通过肝细胞以及对T细胞启动和贩运的影响 PDAC的免疫生物学和癌症免疫疗法的肝细胞激活互补的目标将为旨在减少您减少您的新型治疗范式的发展提供信息免疫服用作用反映了浮力的膨胀，以扩大癌症免疫疗法的疗效。