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

• 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
• 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

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复杂的微环境中，其特征在于缺氧，酸中毒， 以及高的间质压力;所有这些都对T细胞的浸润产生物理屏障。因此， 免疫疗法取决于许多重要因素，包括检查点抑制剂的灌注能力， 通过细胞外基质（ECM）扩散，穿梭于灌注较少的血管或动脉瘤， 免疫抑制微环境，最终识别癌细胞并杀死。胰腺导管 腺癌（PDAC）对化疗和免疫治疗的反应都很差，主要是因为 肿瘤中存在致密间质，缺乏免疫调节性T细胞和细胞因子 微环境（TME）。然而，基质减少剂的使用并不成功，因为 事实上，产生基质的肌成纤维细胞的消耗与免疫抑制和存活无关 胰腺癌的发病率因此，需要确定新的战略，以提高TME的敏感性， PDAC和提高免疫检查点抑制剂的效率。一个被忽视但可能占主导地位的 肿瘤药物递送的屏障，是在肿瘤脉管系统和间质空间内形成的小凝块， 称为瘤内凝块。瘤内纤维蛋白凝块在大多数实体瘤中是常见的，其中PDAC表现出 广泛的纤维蛋白原和纤维蛋白凝块遍布肿瘤间质和肿瘤细胞周围。然而，在这方面， 肿瘤内凝块对血液灌注和缺氧以及抑制抗肿瘤免疫的影响已经 被大大低估了。此外，还没有任何策略可以战胜凝块- 诱导免疫屏障，尽管抗凝剂长期以来一直用于治疗癌症患者的血栓形成。 我们假设肿瘤内凝块作为转运屏障，并引发PDAC以产生抑制性血栓。 微环境有助于逃避免疫监视。我们还假设，增强灌注可以 抗凝治疗可以缓解缺氧，使PDAC TME变为免疫支持性TME， 有利于免疫治疗的疗效。为了验证我们的假设，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 （2）检测血液稀释剂对PDAC中T细胞和巨噬细胞的作用， PDAC亚型，体外;和（3）评估血液稀释剂增强抗PD-1疗效的能力 在KPC和人源化小鼠中，当与化疗联合施用时，抗体的活性增加。成功 这项研究的完成将积极影响新的治疗策略的发展， 血液稀释剂和溶栓与现有的胰腺肿瘤检查点抑制剂，这是没有反应的 到免疫疗法。