Autoinflammation in Human Melanoma

项目总结/摘要 黑色素瘤具有高转移倾向，占皮肤癌相关死亡的80%。尽管 尽管在过去几年中黑色素瘤治疗的进展，但黑色素瘤在临床上仍然是一个挑战。 肿瘤学免疫系统在控制和消除癌症方面起着重要作用。然而，肿瘤 通常通过改变其表型和诱导免疫抑制来逃避/逃避免疫攻击。最近 用免疫检查点抑制剂治疗癌症的突破推动了对 新的治疗靶点，包括适应性和先天免疫系统的负调节因子。我们有 发现人类转移性黑色素瘤细胞自发分泌具有生物活性的白细胞介素（IL）-1β， 由于IL-1受体信号传导的组成性激活而缺乏外源性刺激， 多蛋白复合物，“炎性小体”，表现出“自身炎症”（IL-1β介导的 免疫系统失调）。IL-1β是一种多效性促炎细胞因子， 肿瘤进展、免疫抑制和化学抗性。 外周血是一个信息储存库，代表了由于存在以下因素而改变的系统过程： 肿瘤细胞我们对黑色素瘤患者的全血细胞进行了转录组分析， 人黑色素瘤血液中差异表达的基因。其中，我们鉴定了一种独特的细胞因子IL-37， 其在转移性黑素瘤血液中高度上调。IL-37是IL-1细胞因子家族的同源物。 Dinarello（co-I）的研究小组发现IL-37是一种新型的先天免疫抑制剂。PI的研究小组发现， IL-37是一种新的获得性免疫抑制剂。IL-37在含有IL-1的促炎环境中被诱导。 我们假设IL-37是由人黑色素瘤中的自身炎症诱导的，导致肿瘤诱导的免疫应答。 免疫逃避我们建议使用黑色素瘤患者的肿瘤和血液样本来验证这一假设 (in目的1）并阐明IL-37在肿瘤细胞（目的2）和血液中的免疫逃避作用机制 黑色素瘤中的细胞（在Aim 3中）。具体目标是： 目的1：鉴定人黑色素瘤样本中IL-37表达的细胞来源，并确定IL-37与黑色素瘤的关系。 IL-37与人类黑色素瘤自身炎症的关系。 目的2：研究IL-37对黑色素瘤细胞的生物学作用及其机制。 目的3：确定IL-37在血细胞中的生物学和机制作用。 IL-37是先天性和获得性免疫的抑制剂，尚未在肿瘤免疫中进行研究。阐明 自身炎症和免疫逃逸之间的联系，以及了解IL-37在肿瘤免疫中的作用 逃避对于黑色素瘤的临床成功至关重要， 抗癌药

PROJECT SUMMARY/ABSTRACT Melanoma has a high propensity for metastasis and accounts for 80% of skin cancer-related deaths. Despite the progress in melanoma therapeutics over the last several years, melanoma remains a challenge in clinical oncology. The immune system plays an important role in controlling and eliminating cancer. However, tumors often evade/escape immune attack by modifying their phenotypes and inducing immunosuppression. Recent breakthrough in treating cancers with immune checkpoint inhibitors has fueled the intensive investigation of new therapeutic targets, including negative regulators of adaptive and innate immune systems. We have found that human metastatic melanoma cells spontaneously secrete biologically active interleukin (IL)-1β in the absence of exogenous stimuli because of constitutive activation of IL-1 receptor signaling and a multi-protein complex, “inflammasome”, exhibiting a feature of “autoinflammation” (IL-1β-mediated dysregulation of immune system). IL-1β is a pleiotropic pro-inflammatory cytokine and plays a critical role in tumor progression, immunosuppression and chemoresistance. Peripheral blood is an information reservoir and represents systemic processes altered by the presence of tumor cells. We conducted transcriptome profiling of whole blood cells from melanoma patients, and identified differentially expressed genes in human melanoma blood. Of these, we identified a unique cytokine, IL-37, which was highly upregulated in metastatic melanoma blood. IL-37 is a homolog of the IL-1 cytokine family. Dinarello (co-I)’s group has found that IL-37 is a novel inhibitor of innate immunity. PI’s group has found that IL-37 is a novel inhibitor of adaptive immunity. IL-37 is induced in pro-inflammatory milieu containing IL-1. We hypothesize that IL-37 is induced by autoinflammation in human melanoma, leading to tumor-induced immunoevasion. We propose to test this hypothesis using tumor and blood samples from melanoma patients (in Aim 1) and unravel the immunoevasive mechanisms of action of IL-37 in tumor cells (in Aim 2) and blood cells (in Aim 3) in melanoma. The specific aims are: Aim 1: To identify cellular source of IL-37 expression in human melanoma samples and determine the link between IL-37 and autoinflammation in human melanoma. Aim 2: To define biological and mechanistic effects of IL-37 in melanoma cells. Aim 3: To define biological and mechanistic effects of IL-37 in blood cells. IL-37, an inhibitor of innate and adaptive immunity, has not been investigated in tumor immunity. Elucidating the link between autoinflammation and immune escape, and understanding the role of IL-37 in tumor immune escape is critical for clinical success in melanoma and will lead to the development of effective therapeutic agents for cancer.