Environmental pro-oxidative stressors and immunosuppression

环境促氧化应激源和免疫抑制

基本信息

批准号：
9130895
负责人：
Ravi PRAKASH Sahu
金额：
$ 16.25万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130895
关键词：
Agonist Anaphylaxis Antibodies Antigen Targeting Antioxidants Binding CD8B1 gene Cancer Cell Growth Clinical Clinical Research Cytotoxic T-Lymphocyte-Associated Protein 4 Disease Outcome Dose Effectiveness Enzyme Induction Enzymes Event Exhibits Exposure to Generations Grant Growth Human IL2RA gene Immune Immune response Immunity Immunologics Immunophenotyping Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Interleukin-10 Investigation Knockout Mice Ligands Malignant Neoplasms Mediating Metastatic Melanoma Methods Modeling Mus Myelogenous PDCD1LG1 gene PUVA Photochemotherapy Pathologic Pathway interactions Patients Phospholipids Phototherapy Platelet Activating Factor Play Prevalence Proteins Publishing Radiation Radiation therapy Reactive Oxygen Species Refractory Regulatory T-Lymphocyte Reporting Research Resistance Role Skin Skin Cancer Solid Neoplasm Suppressor-Effector T-Lymphocytes Survival Rate T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenic Mice Tumor Antigens Tumor Escape Tumor Immunity Ultraviolet B Radiation United States Up-Regulation allergic response aryl hydrocarbons base cancer immunotherapy cancer type cell type chemical carcinogen chemotherapeutic agent chemotherapy cigarette smoking clinically relevant curative treatments cyclooxygenase 2 cytokine irradiation lipid mediator melanoma mouse model neoplastic cell novel novel strategies novel therapeutics oxidized lipid patient subsets platelet activating factor receptor preclinical study protective effect public health relevance resistance mechanism response stressor systemic toxicity tool tumor tumor growth tumor microenvironment ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Melanoma is one of the deadliest skin cancers in the United States and unlike most other major cancer types; its prevalence is increasing rapidly. Despite having various treatment options including radiation therapy and chemotherapy, curative treatment for metastatic melanoma remains elusive. Immunotherapy has shown promise in inducing clinical responses in a small subset of patients. However, the overall survival rate of patients with metastatic melanoma is disappointing. Thus, it is important to identify factors which limit the efficacy of immunotherapy such as Ipilimumab. Studies have demonstrated that exposure of pro-oxidative stressors including ultraviolet-B irradiation to human and mouse skin generates oxidized lipid mediators with platelet-activating factor (PAF) agonist activity. These UV-B generated PAF agonists act via PAF-receptor (PAF-R) and mediate systemic immunosuppression via cyclooxygenase 2 (COX-2), immunosuppressive cytokine, interleukin 10 (IL-10) and cell type regulatory T cells (Tregs). Importantly, it has been recently shown that UV-B/PAF-R agonists mediated systemic immunosuppression augments the growth of murine B16F10 melanoma tumors in a PAF-R dependent manner. These effects were mediated via up-regulation of IL-10 and Tregs in the tumor microenvironment. Notably, anti-oxidants and depleting antibodies against IL-10 and Tregs (anti-CD25) blocked UV-B/PAF-R agonists-mediated enhanced tumor growth, indicating the involvement of oxidative generated PAF-R agonists and downstream IL-10 and Tregs in immune evasion of B16F10 tumors. Thus, pro-oxidative stressors may play an important role in inhibiting immune-mediated clearance of melanoma and therefore could potentially compromise the efficacy of melanoma immunotherapy, aimed at suppressing immune escape mechanisms. Notably, it is now demonstrated that UV-B-induces a PAF-R dependent up-regulation of the negative co-stimulatory T-cell receptors CTLA-4 and PD-1 in the tumor microenvironment, which have been demonstrated to suppress normal immune responses against tumor antigens. Importantly, it has been shown that PAF-R agonists' induced systemic immunosuppression is mediated via myeloid derived suppressor cells (MDSCs), an immunophenotype known to suppress host anti-tumor immunity against target antigens. The studies in the proposed grant attempt to take initiative in a direction which could have a major impact on treatment options for melanoma. The preclinical studies outlined below will (1) potentially provide novel strategies to increase the efficacy of anti-CTLA-4 and/or anti-PD-1 melanoma immunotherapy, (2) explore mechanisms of how pro-oxidative stressors can inhibit host anti-tumor immunity. In addition, clinical studies will allow direct assessment of whether therapeutic dose of UV-B can generate adequate levels of immunosuppressive PAF-R agonists in patients undergoing phototherapy. These studies will help in determining the impact of PAF-R agonists on the disease outcomes in patients. These studies will also take advantage of various transgenic and knockout mouse models as a tool for our research.

描述（由申请人提供）：黑色素瘤是美国最致命的皮肤癌之一，与大多数其他主要癌症类型不同。其患病率正在迅速增加。尽管有多种治疗选择，包括放射治疗和化疗，但转移性黑色素瘤的治愈方法仍然难以实现。免疫疗法在一小部分患者中显示出诱导临床反应的希望。然而，转移性黑色素瘤患者的总体生存率令人失望。因此，确定限制免疫疗法（如伊匹单抗）疗效的因素非常重要。研究表明，人类和小鼠皮肤接触促氧化应激源（包括紫外线 B 照射）会产生具有血小板激活因子 (PAF) 激动剂活性的氧化脂质介质。这些 UV-B 产生的 PAF 激动剂通过 PAF 受体 (PAF-R) 发挥作用，并通过环氧合酶 2 (COX-2)、免疫抑制细胞因子、白细胞介素 10 (IL-10) 和细胞类型调节性 T 细胞 (Treg) 介导系统性免疫抑制。重要的是，最近发现 UV-B/PAF-R 激动剂介导的全身免疫抑制以 PAF-R 依赖性方式增强小鼠 B16F10 黑色素瘤的生长。这些作用是通过肿瘤微环境中 IL-10 和 Tregs 的上调介导的。值得注意的是，抗氧化剂和针对 IL-10 和 Tregs 的消耗性抗体（抗 CD25）阻断了 UV-B/PAF-R 激动剂介导的肿瘤生长增强，表明氧化产生的 PAF-R 激动剂和下游 IL-10 和 Treg 的参与。 B16F10 肿瘤免疫逃避中的 Tregs。因此，促氧化应激源可能在抑制免疫介导的黑色素瘤清除中发挥重要作用，因此可能会损害旨在抑制免疫逃逸机制的黑色素瘤免疫治疗的功效。值得注意的是，现在已经证明，UV-B 会诱导肿瘤微环境中负性共刺激 T 细胞受体 CTLA-4 和 PD-1 的 PAF-R 依赖性上调，这已被证明可以抑制正常免疫针对肿瘤抗原的反应。重要的是，研究表明，PAF-R 激动剂诱导的全身免疫抑制是通过骨髓源性抑制细胞 (MDSC) 介导的，MDSC 是一种已知可抑制宿主针对靶抗原的抗肿瘤免疫的免疫表型。拟议拨款中的研究试图朝着可能对黑色素瘤治疗方案产生重大影响的方向采取主动。下面概述的临床前研究将（1）潜在地提供新的策略来提高抗 CTLA-4 和/或抗 PD-1 黑色素瘤免疫疗法的功效，（2）探索促氧化应激源如何抑制宿主抗肿瘤免疫。此外，临床研究将允许直接评估治疗剂量的 UV-B 是否可以在接受光疗的患者中产生足够水平的免疫抑制 PAF-R 激动剂。这些研究将有助于确定 PAF-R 激动剂对患者疾病结果的影响。这些研究还将利用各种转基因和基因敲除小鼠模型作为我们研究的工具。