The Adenosinergic Pathway in Tumor-derived Exosomes

肿瘤源性外泌体中的腺苷能途径

• 批准号: 10589774
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 49.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589774
• 关键词: Adenosine; Apoptosis; Automobile Driving; B-Lymphocytes; Biochemical Pathway; Biogenesis; Biological Assay; Biological Markers; Blood; Body Fluids; CD8B1 gene; Cancer Patient; Cell Line; Cell physiology; Cell surface; Cells; Chemistry; Communication; Cyclic ADP-Ribose; Cyclic AMP; Data; Disease; Distant; Effector Cell; Enzymes; Erythrocytes; Exhibits; G-Protein-Coupled Receptors; Growth; Half-Life; Human; Immune; Immune Cell Suppression; Immune System Diseases; Immune Targeting; Immune checkpoint inhibitor; Immune system; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Laboratories; Ligands; Link; Macrophage; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Messenger RNA; Metabolism; Methods; Molecular; Mus; Names; Natural Killer Cells; Neoplasm Metastasis; Normal Cell; Nucleic Acids; Parents; Pathway interactions; Patients; Performance; Phenotype; Plasma; Play; Prognosis; Proliferating; Proteins; Purinergic P1 Receptors; Purines; Regulatory T-Lymphocyte; Role; Sampling; Signaling Molecule; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tumor Escape; Tumor Promotion; Tumor-Derived; Tumor-infiltrating immune cells; angiogenesis; cancer biomarkers; cancer therapy; carcinogenesis; checkpoint inhibition; exosome; extracellular vesicles; growth promoting activity; immune checkpoint; immune function; immunoregulation; improved; in vivo; insight; melanoma; mouse model; neoplastic cell; new therapeutic target; novel; potential biomarker; prognosis biomarker; rational design; receptor; response; treatment response; tumor; tumor growth; tumor immunology; tumor progression; uptake

PROJECT SUMMARY/ABSTRACT Tumor cells produce and release large numbers of extracellular vesicles (EVs). A subset of small (30-150 nm) EVs derived from the endocytic compartment of the tumor cell is called TEX (Tumor-derived Exosomes). TEX carry various immunoregulatory molecules and relative to normal cell-derived exosomes, NTEX (Non-Tumor cell-derived Exosomes), are enriched in inhibitory proteins which suppress functions of immune effector cells. TEX have recently emerged as a major immunosuppressive system used by tumors to escape from the host immune system. Our results indicate that adenosine (ADO), now considered a major immune checkpoint in cancer, and the enzymes driving the adenosinergic pathway are carried and delivered to target immune cells by TEX. We hypothesize that TEX-mediated suppression of immune cells in cancer is due to ADO distributed by TEX, which thereby encourage tumor growth and metastasis. We will test this hypothesis first by comparing the adenosinergic pathway activity in TEX versus NTEX isolated from plasma of patients with melanoma by a unique immune capture method we have developed. In concert with newly introduced highly sensitive etheno-bridge chemistry and a state-of-the-art UPLC-MS/MS system, we now have means to measure the activity of the canonical and non-canonical ADO-producing biochemical pathways in paired TEX versus NTEX of each patient. We will define “adenosinergic drive” as the capacity of TEX to produce immunosuppressive ADO and will link it to in vitro functional assays performed with each patient’s immune cells. The discovery in Aim 1 of high adenosinergic drive in melanoma patients TEX relative to NTEX is expected to confirm the major role of TEX in tumor immune escape. Aim 1 will also provide an in vitro measure of adenosinergic drive in every melanoma patient for use in Aims 2 and 3 studies. In Aim 2, TEX with “high” versus “low” adenosinergic drive will be injected IV into mice to determine their in vivo effects on carcinogenesis, cancer growth, angiogenesis, immune dysfunction and metastasis formation. This Aim extends the role of TEX from immune suppression to tumor growth promoting activities. Various well-established mouse models will be used to measure adenosinergic activity of TEX in vivo. We will also examine whether in vivo blocking of the adenosine pathway reverses detrimental effects mediated by TEX. In Aim 3, we will assess the utility of adenosinergic drive in TEX as a biomarker of prognosis and response to immune checkpoint inhibitors. Utilizing TEX isolated from banked plasma of melanoma patients, we will correlate adenosinergic drive in the TEX with disease stage and clinicopathological endpoints as well as with prognosis and response to immunotherapy. By elucidating the role of TEX in ADO-mediated immune suppression as well as tumor progression in cancer, this study introduces new therapeutic targets and new cancer biomarkers that are expected to improve cancer therapy and patient survival.

项目摘要/摘要 肿瘤细胞产生并释放大量细胞外蔬菜（EV）。小（30-150 nm）的子集 源自肿瘤细胞内吞区室的电动汽车称为Tex（肿瘤衍生的外泌体）。 携带各种免疫调节分子，相对于正常细胞衍生的外泌体NTEX（非肿瘤） 细胞来源的外泌体），富含抑制性蛋白的抑制性蛋白质，这些蛋白抑制了免疫效应细胞的功能。 Tex最近成为肿瘤用来逃离宿主的主要免疫抑制系统 免疫系统。我们的结果表明，腺苷（ADO）现在被认为是一个主要的免疫检查站 癌症和驱动腺苷能途径的酶被携带，并通过 Tex。我们假设Tex介导的癌症抑制癌症是由于ADO造成的 Tex，从而鼓励肿瘤生长和转移。我们将首先通过比较 通过独特的独特 我们开发的免疫捕获方法。与新推出的高度敏感的埃塞诺桥一起 化学和最先进的UPLC-MS/MS系统，我们现在有手段来衡量 每个患者的配对Tex与NTEX的规范和非典型的生物化学途径。 我们将“将“腺力能驱动”定义为Tex产生免疫抑制ADO的能力，并将其联系起来 对每个患者的免疫细胞进行的体外功能测定。 AIM 1的发现 黑色素瘤患者Tex相对于NTEX的腺苷能驱动预计将确认Tex在 肿瘤免疫逃生。 AIM 1还将在每个黑色素瘤中对腺苷能驱动的体外测量 患者用于目标2和3研究。在AIM 2中，具有“高”与“低”腺苷能驱动的Tex将是 将静脉注射到小鼠中，以确定其体内对癌变，癌症生长，血管生成，免疫的影响 功能障碍和转移形成。这个目标将TEX的作用从免疫抑制到肿瘤 增长促进活动。各种公认的鼠标模型将用于测量腺苷能 Tex在体内的活动。我们还将检查腺苷途径的体内阻塞是否逆转 Tex介导的有害效应。在AIM 3中，我们将评估Tex的腺苷能量驱动器的效用 预后的生物标志物和对免疫检查点抑制剂的反应。利用与银行隔离的Tex 黑色素瘤患者的血浆，我们将与疾病阶段和 临床病理学终点以及预后和对免疫疗法的反应。通过阐明角色 在Ado介导的免疫抑制以及癌症中的肿瘤进展中，本研究引入了新的 预计将改善癌症治疗和患者生存的治疗靶标和新的癌症生物标志物。