Environmental pro-oxidative stressors and immunosuppression

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。尽管有各种治疗选择，包括放射疗法和化学疗法，但转移性黑色素瘤的治愈性治疗仍然难以捉摸。免疫疗法已显示出在一小部分患者中诱导临床应答的前景。然而，转移性黑色素瘤患者的总体生存率令人失望。因此，重要的是要确定限制免疫疗法如伊匹单抗的功效的因素。研究表明，暴露于促氧化应激源，包括紫外线-B照射人类和小鼠皮肤产生氧化脂质介质与血小板活化因子（PAF）激动剂活性。这些UV-B产生的PAF激动剂通过PAF受体（PAF-R）起作用，并通过环氧合酶2（考克斯-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（T细胞）介导全身性免疫抑制。重要的是，最近已经显示UV-B/PAF-R激动剂介导的全身性免疫抑制以PAF-R依赖性方式增强鼠B16 F10黑素瘤肿瘤的生长。这些作用是通过肿瘤微环境中IL-10和TcR的上调介导的。值得注意的是，抗氧化剂和针对IL-10和Tcl 3（抗CD 25）的消耗性抗体阻断UV-B/PAF-R激动剂介导的增强的肿瘤生长，表明氧化产生的PAF-R激动剂和下游IL-10和Tcl 3参与B16 F10肿瘤的免疫逃避。因此，促氧化应激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疗效。值得注意的是，现在证明UV-B诱导肿瘤微环境中负共刺激T细胞受体CTLA-4和PD-1的PAF-R依赖性上调，其已被证明抑制针对肿瘤抗原的正常免疫应答。重要的是，已经显示PAF-R激动剂诱导的全身性免疫抑制是通过髓源性抑制细胞（MDSC）介导的，所述髓源性抑制细胞是已知抑制针对靶抗原的宿主抗肿瘤免疫的免疫表型。拟议拨款中的研究试图在一个可能对黑色素瘤治疗选择产生重大影响的方向上采取主动。以下概述的临床前研究将（1）潜在地提供新的策略以增加抗CTLA-4和/或抗PD-1黑色素瘤免疫疗法的功效，（2）探索促氧化应激如何抑制宿主抗肿瘤免疫的机制。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性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。

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.