Targeting ILlRAP in virus-associated malignancies

摘要 卡波西肉瘤相关疱疹病毒(KSHV)是几种人类癌症的病原体，包括 Kaposi肉瘤(KS)和原发性渗出性淋巴瘤(PEL)，好发于 免疫功能受损的患者，缺乏有效的治疗选择。KS也代表了一种常见的口腔 艾滋病患者中的癌症。PEL是一种进展迅速的B细胞性淋巴瘤，预后较差 即使在联合化疗下也是如此。白介素1(Interleukin1，IL1)家族是一种重要的细胞因子 炎症，在先天免疫和获得性免疫中都发挥着重要作用。白介素1受体附件 蛋白(IL1RAP)作为IL1信号的全球调节因子，包括IL1等许多IL1家族成员， IL33和IL36。然而，IL1受体/辅受体和其他相关配体，特别是IL1RAP在血管内皮细胞中的作用 KSHV的发病机制和肿瘤发生几乎仍不清楚。我们的初步数据显示 在潜伏和裂解条件下，KSHV感染细胞中包括IL1RAP在内的许多IL1信号分子的水平。 IL1信号受体/辅助受体(如IL1R1和IL1RAP)的直接下调显著降低 KSHV淋巴瘤细胞生长。对于临床意义，IL1R1和IL1RAP蛋白都被发现高度 在AIDS-KS组织中的表达与正常皮肤组织相比。基于这些数据，我们假设 包括IL1RAP在内的IL1信号分子在KSHV的发病机制中起重要作用 肿瘤发生，这可能是有吸引力的治疗靶点。为了解决这一假设，我们建议 具体目的如下：1)鉴定IL1RAP在KSHV感染细胞中的功能及其临床意义 与KSHV相关恶性肿瘤的相关性。2)探讨新型IL1RAP抗体BI-BI的治疗效果。 5041，体内抗KSHV相关恶性肿瘤。通过这些努力，我们的目标是阐明 白介素1信号(尤其是白介素1RAP)在KSHV致病机制及病毒相关疾病发展中的作用 恶性肿瘤。我们还将揭示IL1信号在这些病毒感染者中的临床相关性和意义。 相关的恶性肿瘤。此外，这些研究将为制定 针对IL1信号尤其是IL1RAP的干预策略改善KSHV相关的治疗 高危免疫受损患者中的恶性肿瘤。

Abstract Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients and lack of effective therapeutic options. KS also represents one of common oral cancers in AIDS patients. PEL represents a rapidly progressing B cell-derived lymphoma with poor prognosis even under the combinational chemotherapy. Interleukin1 (IL1) family represents a major mediator for inflammation and plays an important role in both innate and adaptive immunity. The IL1 receptor accessory protein (IL1RAP) acts as a global regulator of IL1 signaling, including many of IL1 family members such as IL1, IL33 and IL36. However, the role of IL1 receptor/co-receptor and other related ligands, especially IL1RAP, in KSHV pathogenesis and tumorigenesis remains almost unknown. Our preliminary data indicate the elevated levels of many IL1 signaling molecules including IL1RAP in KSHV-infected cells at both latent and lytic conditions. Direct knock-down of IL1 signaling receptors/co-receptors such as IL1R1 and IL1RAP significantly reduce KSHV+ lymphoma cell growth. For clinical implication, both IL1R1 and IL1RAP proteins are found highly expressed in AIDS-KS tissue when compared to normal skin tissue. Based on these data, we hypothesize that the IL1 signaling molecules including IL1RAP have important role in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets. To address this hypothesis, we propose the following Specific Aims: 1) To identify the functions of IL1RAP in KSHV-infected cells as well as its clinical relevance in KSHV-related malignancies. 2) To explore the therapeutic efficacy of a new IL1RAP antibody, BI- 5041, against KSHV-related malignancies in vivo. Through these efforts, we aim to illuminate putative mechanisms of IL1 signaling (in particular IL1RAP) in KSHV pathogenesis and the development of virus-related malignancies. We will also reveal clinical relevance and implication of IL1 signaling in patients with these virus- associated malignancies. Additionally, these studies will provide a framework for the development of interventional strategies targeting IL1 signaling especially IL1RAP for improving the treatment of KSHV-related malignancies in high-risk immunocompromised patients.