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

项目摘要 皮肤T细胞淋巴瘤（CTCL）是一种无法治愈的疾病，其特征是肿瘤性T细胞定位， 淋巴细胞到皮肤。患者表现出进行性疾病模式，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， 需要治疗来控制由这种疾病引起的使人衰弱的皮肤病变， 更好地了解肿瘤性T细胞定位于皮肤和疾病进展的机制。给定 我们的新发现强调了肿瘤源性白细胞介素-15（IL-15）信号在CTCL进展中的作用， 皮肤，这一途径提供了一个机会，了解炎症细胞因子在皮肤中的作用- CTCL的向性。使用IL-15转基因小鼠模型，我们先前表明IL-15过表达 诱导表型模拟人CTCL的自发性CTCL。IL-15转基因小鼠表现出早期的 肿瘤性T细胞积聚和持续性角质形成细胞增生，导致免疫细胞募集 和皮肤炎症。IL-15在CTCL患者中也长期升高，并且肿瘤性T细胞衍生因子 会导致皮肤发炎我们发现了一种新的信号级联，其中IL-15诱导 恶性T细胞上的皮肤归巢趋化因子受体的组成性激活，从而促进其 CTCL中皮肤的配体依赖性定位。IL-15的药理学抑制阻断了这种信号传导 这是一种细胞增殖途径，从而防止细胞迁移和角质形成细胞增殖。为了充分建立这条道路及其 在CTCL进展中的作用，我们将- 1）阐明CTCL中IL-15产生的机制，2）评估 IL-15对淋巴瘤细胞向皮肤迁移的影响，3）阐明CTCL进展的IL-15依赖性机制 4）了解这是如何导致慢性皮肤炎症的，5）评估 CTCL治疗中阻断IL-15通路。拟议的研究将扩大我们对以下问题的基本认识： 控制皮肤中CTCL进展的机制，并为开发新的抗CTCL药物奠定基础。 在CTCL治疗中抑制致癌信号传导的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.