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：
8679252
负责人：
Ravi PRAKASH Sahu
金额：
$ 16.25万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8679252
关键词：
Agonist Anaphylaxis Antibodies Antigen Targeting Antioxidants Binding CD8B1 gene Cancer Cell Growth Clinical Clinical Research 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 Pathologic Pathway interactions Patients Phospholipids Photochemotherapy 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 Toxic effect 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 cyclooxygenase 2 cytokine irradiation lipid mediator melanoma mouse model neoplastic cell novel novel strategies oxidized lipid platelet activating factor receptor preclinical study protective effect public health relevance resistance mechanism response stressor tool tumor tumor growth tumor microenvironment ultraviolet

项目摘要

Abstract 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. Our 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 UVB 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, we have recently shown that UVB/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 UVB/PAF-R agonists-mediated enhanced tumor growth, indicating the involvement of oxidatively 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, we now demonstrate that UVB-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, we show 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 UVB 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 take an advantage of various transgenic and knockout mouse models as a tool for our research.

抽象的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，转移性黑色素瘤的治愈性治疗仍然难以捉摸。免疫疗法已显示有望在一小部分患者中诱导临床反应。然而，总体生存率转移性黑色素瘤患者的情况令人失望。因此，重要的是要确定限制因素免疫疗法如伊匹单抗（Ipilimumab）的疗效。我们的研究表明，暴露于促氧化物质人类和小鼠皮肤受到的应激源（包括紫外线 B 射线照射）会产生氧化脂质介质血小板激活因子（PAF）激动剂活性。这些 UVB 产生的 PAF 激动剂通过 PAF 受体发挥作用 (PAF-R) 并通过环氧合酶 2 (COX-2) 介导全身免疫抑制，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)。重要的是，我们最近展示了 UVB/PAF-R 激动剂介导的全身免疫抑制可增强小鼠 B16F10 的生长黑色素瘤以 PAF-R 依赖性方式。这些作用是通过 IL-10 的上调介导的肿瘤微环境中的Tregs。值得注意的是，针对 IL-10 和 Tregs 的抗氧化剂和消耗抗体（抗 CD25）阻断 UVB/PAF-R 激动剂介导的肿瘤生长增强，表明参与氧化生成的 PAF-R 激动剂以及下游 IL-10 和 Tregs 在 B16F10 肿瘤的免疫逃避中的作用。因此，促氧化应激源可能在抑制免疫介导的清除黑色素瘤，因此可能会损害黑色素瘤免疫疗法的功效，旨在抑制免疫逃逸机制。值得注意的是，我们现在证明 UVB 诱导 PAF-R 肿瘤中负性共刺激 T 细胞受体 CTLA-4 和 PD-1 的依赖性上调微环境，已被证明可以抑制针对肿瘤的正常免疫反应抗原。重要的是，我们发现 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)，一种已知可抑制宿主抗肿瘤免疫的免疫表型针对目标抗原。拟议拨款中的研究试图在一个方向上采取主动，对黑色素瘤的治疗选择产生重大影响。下面概述的临床前研究将 (1) 可能提供提高抗 CTLA-4 和/或抗 PD-1 黑色素瘤疗效的新策略免疫疗法，（2）探索促氧化应激源如何抑制宿主抗肿瘤免疫的机制。在此外，临床研究将允许直接评估治疗剂量的 UVB 是否可以产生接受光疗的患者体内有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。