Priming pancreatic ductal adenocarcinoma using blood thinners to sensitize the efficacy of checkpoint immunotherapy

使用血液稀释剂引发胰腺导管腺癌以提高检查点免疫疗法的疗效

基本信息

批准号：
10333749
负责人：
Taslim A Al-Hilal
金额：
$ 35.65万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333749
关键词：
Accounting Acidosis Affect Anticoagulants Anticoagulation Attenuated Blood Platelets Blood Vessels Cancer Etiology Cancer Patient Cells Cessation of life Clinical Coagulation Process Complex Cytotoxic T-Lymphocytes Deep Vein Thrombosis Deposition Development Diffuse Disease Drug Delivery Systems Drug Transport Exhibits Extracellular Matrix Fibrin Fibrinogen Gene Expression Genes Hemostatic function Human Hypoxia Immune Immune Evasion Immune checkpoint inhibitor Immunologic Surveillance Immunosuppression Immunotherapy Impairment In Vitro Invaded KPC model Lung Malignant Neoplasms Malignant neoplasm of pancreas Mesenchymal Myelogenous Myofibroblast Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Patients Perfusion Phase II Clinical Trials Proteins Reducing Agents Reporting Solid Neoplasm Stromal Cells Survival Rate T-Cell Activation T-Lymphocyte Testing Thrombosis Thrombus Transgenic Mice Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells Vascular Endothelium Vascular blood supply Veins anti-PD1 antibodies blood perfusion cancer cell cancer immunotherapy cancer therapy checkpoint therapy chemotherapy clinical practice clinically relevant cytokine design humanized mouse immune checkpoint immunoregulation improved insight interstitial macrophage mouse model neoplastic cell pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pre-clinical pressure response thrombocytosis thrombotic complications tissue repair treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions wound healing

Accounting Acidosis Affect Anticoagulants Anticoagulation Attenuated Blood Platelets Blood Vessels Cancer Etiology Cancer Patient Cells Cessation of life Clinical Coagulation Process Complex Cytotoxic T-Lymphocytes Deep Vein Thrombosis Deposition Development Diffuse Disease Drug Delivery Systems Drug Transport Exhibits Extracellular Matrix Fibrin Fibrinogen Gene Expression Genes Hemostatic function Human Hypoxia Immune Immune Evasion Immune checkpoint inhibitor Immunologic Surveillance Immunosuppression Immunotherapy Impairment In Vitro Invaded KPC model Lung Malignant Neoplasms Malignant neoplasm of pancreas Mesenchymal Myelogenous Myofibroblast Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Patients Perfusion Phase II Clinical Trials Proteins Reducing Agents Reporting Solid Neoplasm Stromal Cells Survival Rate T-Cell Activation T-Lymphocyte Testing Thrombosis Thrombus Transgenic Mice Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells Vascular Endothelium Vascular blood supply Veins anti-PD1 antibodies blood perfusion cancer cell cancer immunotherapy cancer therapy checkpoint therapy chemotherapy clinical practice clinically relevant cytokine design humanized mouse immune checkpoint immunoregulation improved insight interstitial macrophage mouse model neoplastic cell pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pre-clinical pressure response thrombocytosis thrombotic complications tissue repair treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions wound healing

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项目摘要

Project Summary: Cancer and stromal cells co-exist within a complex microenvironment that is characterized by hypoxia, acidosis, and high interstitial pressure; all of which generate a physical barrier to T cells' infiltration. Thus, the efficacy of an immunotherapy depends on many vital factors, including the ability of the checkpoint inhibitor to perfuse and diffuse through the extracellular matrix (ECM), shuttle through the less perfused vessels or interstitia, attenuate the immunosuppressive microenvironment and finally, recognize cancer cells to kill. Pancreatic ductal adenocarcinomas (PDACs) are poorly responsive to both chemo- and immunotherapies, mainly because of the presence of dense stroma and absence of immunomodulatory T-cells and cytokines in the tumor microenvironment (TME). However, the use of stroma-reducing agents has not been successful because of the fact that depletion of stroma-producing myofibroblasts did not correlate with immunosuppression and survival rate in pancreatic cancers. Thus, there is an unmet need to identify new strategies that can sensitize the TME of PDAC and increase the efficiency of immune checkpoint inhibitors. A largely overlooked, but potentially dominant barrier to tumoral drug delivery, are the small clots that form within the tumor vasculature and interstitial space, called intratumoral clots. Intratumoral fibrin clots are common in the most solid tumors, where PDACs exhibit extensive fibrinogen and fibrin clots throughout the tumor stroma and surrounding of the tumor cells. However, the impact of intratumoral clots on blood perfusion and hypoxia and in dampening the anti-tumor immunity has been immensely underestimated. Furthermore, no strategies have been in use that can outmaneuver clot- induced immune-barriers although anticoagulants have long been used to treat thrombosis in cancer patients. We hypothesize that intratumoral clots act as a transport barrier and prime the PDACs to create a suppressive microenvironment that helps to escape immune surveillance. We also hypothesize that enhanced perfusion sue to anticoagulation can alleviate hypoxia and alter the PDAC TME into an immune-supportive one, which will also benefit the efficacy of immunotherapy. To test our hypothesis, we designed three specific aims: (1) To study the clinical and pre-clinical relevance of fibrin deposition on regulating PDAC immunosuppressive microenvironment and tumor progression in PDAC; (2) To test the effects of blood thinners on T cells and macrophages against PDAC subtypes, in vitro; and (3) To assess the ability of blood thinners in potentiating the efficacy of anti-PD-1 antibody when administered in combination with chemotherapy in KPC and humanized mice. Successful completion of this study will positively affect the development of new treatment strategy combining ‘off-the-shelf’ blood thinners and thrombolytic with existing checkpoint inhibitors for pancreatic tumors, which are unresponsive to immunotherapy.

项目摘要：癌症和基质细胞在复杂的微环境中共存，其特征是缺氧，酸中毒，和高间隙压力；所有这些都产生了T细胞浸润的物理障碍。那，效率免疫疗法取决于许多重要因素，包括检查点抑制剂灌注和通过细胞外基质（ECM）扩散，穿过灌注较少的血管或跨齿的穿梭，减弱免疫抑制性微环境，最后识别癌细胞杀死。胰管导管腺癌（PDAC）对化学疗法和免疫疗法的反应不佳，主要是因为肿瘤中存在致密的基质以及没有免疫调节的T细胞和细胞因子微环境（TME）。但是，使用减质剂的使用并没有成功，因为造成基质肌纤维细胞的耗竭的事实与免疫抑制和生存无关胰腺癌的速率。那就是确定可以感觉到TME的新策略的未满足的需求 PDAC并提高免疫切除剂抑制剂的效率。在很大程度上被忽视，但可能占主导地位肿瘤药物输送的障碍是在肿瘤脉管系统和间质空间内形成的小部分，称为肿瘤内凝块。肿瘤内纤维蛋白凝块在最实体瘤中很常见，PDAC表现出整个肿瘤基质及其周围的纤维蛋白原和纤维蛋白布的广泛纤维蛋白原和纤维蛋白布。然而，肿瘤内血块对血液灌注和缺氧的影响以及抗肿瘤免疫的影响被低估了。此外，没有使用任何策略来超越克隆尽管抗凝剂长期以来一直用于治疗癌症患者的血栓形成，但诱导的免疫助攻。我们假设肿瘤内凝块充当运输屏障，并在PDAC上启动抑制性有助于避免免疫监视的微环境。我们还假设增强的灌注苏抗凝可以减轻缺氧并将PDAC TME改变为免疫支持的，这也将有益于免疫疗法的效率。为了检验我们的假设，我们设计了三个具体目标：（1）研究纤维蛋白沉积对调节PDAC免疫抑制微环境的临床和临床前相关性 PDAC中的肿瘤进展；（2）测试血液稀释剂对T细胞和巨噬细胞的影响 PDAC亚型，体外；（3）评估抗PD-1效率的血液稀释剂的能力抗体与KPC和人源化小鼠的化学疗法结合施用。成功的这项研究的完成将对结合“现成”的新治疗策略的制定产生积极影响胰腺肿瘤现有检查点抑制剂的血液稀释剂和溶栓剂，这是无反应的进行免疫疗法。