The Role of IL-15 in Cutaneous T-cell Lymphoma Progression

项目总结 皮肤T细胞淋巴瘤(CTCL)是一种以肿瘤性T细胞为特征的难治性疾病 淋巴细胞进入皮肤。患者表现出一种进行性疾病模式，仅限于皮肤，通常需要生命- 治疗时间长，严重影响生活质量。鉴于CTCL的发病率正在上升，而且是长期的 需要治疗来管理由这种疾病引起的衰弱的皮肤损害，迫切需要 为了更好地了解肿瘤T细胞定位于皮肤和疾病进展的机制。vt.给出 我们的新发现强调了肿瘤衍生的白介素15(IL-15)信号在CTCL进展中的作用 皮肤，这个途径提供了一个机会来了解炎症细胞因子在皮肤中的作用- CTCL的趋向性。使用IL-15的转基因小鼠模型，我们先前发现IL-15过度表达 诱导一种自发的CTCL，其表型与人类CTCL相似。IL-15转基因小鼠表现出早期的 肿瘤T细胞积聚和持续角质形成细胞增生，导致免疫细胞募集 和皮肤炎。CTCL患者IL-15也慢性升高，肿瘤T细胞衍生因子 都会导致皮肤发炎。我们发现了一种新的信号级联反应，IL-15在其中诱导 皮肤归巢趋化因子受体在恶性T细胞上的结构性激活，从而促进其 CTCL的皮肤定位依赖于配体。IL-15的药理抑制可阻断这一信号 途径，从而阻止细胞迁移和角质形成细胞的增殖。要完全建立这条途径及其 在CTCL进展中的作用，我们将-1)阐明CTCL中IL-15的产生机制，2)评估其影响 IL-15对淋巴瘤细胞向皮肤迁移的影响，3)阐明IL-15在CTCL进展中的依赖机制 在皮肤方面，4)了解这如何导致慢性皮肤炎，以及5)评估 阻断IL-15通路在CTCL治疗中的作用拟议的研究将扩大我们对以下问题的基本理解 控制CTCL在皮肤中进展的机制将为开发新型抗肿瘤药物奠定基础 在CTCL治疗中抑制致癌信号的IL-15疗法。

PROJECT SUMMARY Cutaneous T-cell Lymphoma (CTCL) is an incurable disease characterized by the localization of neoplastic T lymphocytes to the skin. Patients display a progressive disease pattern, limited to the skin, often requiring life- long treatment, significantly impacting the quality of life. Given that the incidence of CTCL is rising and long-term treatments are needed to manage the debilitating skin lesions caused by this disease, there is an urgent need to better understand the mechanisms of neoplastic T-cell localization to the skin and disease progression. Given our new findings highlighting the role of tumor-derived interleukin-15 (IL-15) signaling in CTCL progression in the skin, this pathway presents an opportunity to understand the role of inflammatory cytokines in the skin- tropism of CTCL. Using a transgenic mouse model of IL-15, we previously showed that IL-15 overexpression induces a spontaneous CTCL that phenotypically mimics human CTCL. IL-15 transgenic mice show an early accumulation of neoplastic T-cells and persistent keratinocyte hyperplasia, resulting in immune cell recruitment and skin inflammation. IL-15 is also chronically elevated in CTCL patients, and neoplastic T-cells derived factors are suggested to cause skin inflammation. We have discovered a new signaling cascade in which IL-15 induces constitutive activation of skin-homing chemokine receptors on the malignant T-cells, thereby promoting their ligand-dependent localization to the skin in CTCL. Pharmacological inhibition of IL-15 blocks this signaling pathway, thereby preventing cell migration and keratinocyte proliferation. To fully establish this pathway and its role in CTCL progression, we will - 1) elucidate mechanisms of IL-15 production in CTCL, 2) evaluate the impact of IL-15 on lymphoma cell migration to the skin, 3) clarify the IL-15 dependent mechanisms of CTCL progression in the skin, 4) understand how this leads to chronic skin inflammation, and 5) evaluate therapeutic potential of blocking IL-15 pathway in CTCL treatment. The proposed studies will expand our fundamental understanding of the mechanisms that control CTCL progression in the skin and will lay the foundation for developing novel anti- IL-15 therapies that inhibit oncogenic signaling in the treatment of CTCL.