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：
10659108
负责人：
Taslim A Al-Hilal
金额：
$ 38.38万
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/10659108
关键词：
Accounting Acidosis Affect Anticoagulants Anticoagulation Attenuated Blood Platelets Blood Vessels Cancer Etiology Cancer Patient Cells Cessation of life 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 Adenocarcinoma Macrophage 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 infiltration T-Cell Activation T-Lymphocyte Testing Thrombosis Thrombus Transgenic Mice Tumor Immunity Tumor Tissue United States 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 cell infiltrate immune checkpoint immunoregulation improved insight interstitial mouse model neoplastic cell novel therapeutic intervention pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm platelet function pre-clinical pressure repair function response thrombocytosis thrombotic complications tissue repair tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions wound healing

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.

项目概要：癌症和基质细胞共存于一个复杂的微环境中，其特征是缺氧、酸中毒、和高间质压力；所有这些都会对 T 细胞的浸润产生物理屏障。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间质，减弱免疫抑制微环境，最后识别并杀死胰腺导管细胞。腺癌（PDAC）对化疗和免疫疗法的反应都很差，主要是因为肿瘤中存在致密基质且缺乏免疫调节 T 细胞和细胞因子然而，由于基质减少剂的使用尚未成功。事实上，产生基质的肌成纤维细胞的消耗与免疫抑制和生存无关因此，寻找能够使 TME 敏感的新策略的需求尚未得到满足。 PDAC 和提高免疫检查点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凝块，肿瘤内纤维蛋白凝块在大多数实体瘤中很常见，其中 PDAC 表现出这种情况。广泛的纤维蛋白原和纤维蛋白凝块遍及肿瘤基质和肿瘤细胞周围。瘤内血栓对血液灌注和缺氧以及抑制抗肿瘤免疫的影响此外，目前还没有任何策略能够战胜血栓。尽管抗凝剂长期以来一直用于治疗癌症患者的血栓形成，但诱导免疫屏障。我们研究肿瘤内凝块作为运输屏障并启动 PDAC 以产生抑制性我们还捕获了有助于逃避免疫监视的微环境。抗凝治疗可以缓解缺氧并将 PDAC TME 转变为免疫支持型 TME，这也将为了检验我们的假设，我们设计了三个具体目标：（1）研究纤维蛋白沉积与调节 PDAC 免疫抑制微环境的临床和临床前相关性 (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；以及 (3) 评估血液稀释剂增强抗 PD-1 功效的能力抗体与 KPC 和人源化小鼠的化疗联合使用时取得了成功。这项研究的完成将对结合“现成”的新治疗策略的开发产生积极影响血液稀释剂和溶栓剂与现有的检查点抑制剂对胰腺肿瘤没有反应到免疫治疗。