Environmental pro-oxidative stressors and immunosuppression

环境促氧化应激源和免疫抑制

• 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
• 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

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.

摘要 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， 它的流行正在迅速增加。尽管有各种治疗选择，包括放射治疗和 转移性黑色素瘤的化疗和根治方法仍然难以捉摸。免疫疗法显示 承诺在一小部分患者中诱导临床反应。然而，总的存活率， 转移性黑色素瘤患者令人失望。因此，重要的是找出限制 免疫治疗的疗效，如伊匹单抗。我们的研究表明，接触促氧化物质 包括紫外线B辐射在内的应激源对人和小鼠皮肤产生氧化脂质介质 血小板活化因子(PAF)激动剂活性。这些UVB产生的PAF激动剂通过PAF受体起作用 (PAF-R)和通过环氧合酶2(COX-2)介导的全身免疫抑制，免疫抑制 细胞因子、白介素10(IL-10)和细胞类型调节性T细胞(Tregs)。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促进小鼠B16F10的生长 黑色素瘤以PAF-R依赖的方式发生。这些作用是通过上调IL-10和 肿瘤微环境中的Tregs。值得注意的是，抗氧化剂和针对IL-10和Tregs的耗竭抗体 (抗CD25)阻断UVB/PAF-R激动剂介导的促进肿瘤生长，表明参与了 氧化生成的PAF-R激动剂及其下游IL-10和Tregs在B16F10肿瘤免疫逃逸中的作用 因此，促氧化应激源可能在抑制免疫介导的清除 黑色素瘤，因此可能潜在地损害黑色素瘤免疫治疗的疗效，目的是 抑制免疫逃逸机制。值得注意的是，我们现在证明了UVB诱导的PAF-R 肿瘤中负共刺激T细胞受体CTLA-4和PD-1的依赖性上调 微环境，已被证明抑制了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 髓系来源的抑制细胞(MDSCs)，一种已知抑制宿主抗肿瘤免疫的免疫表型 抗目标抗原。拟议拨款中的研究试图朝着一个方向采取主动，可以 对黑色素瘤的治疗选择有重大影响。以下概述的临床前研究将(1) 潜在地提供了提高抗CTLA-4和/或抗PD-1黑色素瘤疗效的新策略 免疫治疗，(2)探索促氧化应激源如何抑制宿主抗肿瘤免疫的机制。在……里面 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 在接受光疗的患者中适当水平的免疫抑制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局的影响。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。