SOCS1 is a crucial regulator for uveal melanoma response to immunotherapy

SOCS1是葡萄膜黑色素瘤对免疫治疗反应的关键调节因子

基本信息

  • 批准号:
    10412591
  • 负责人:
  • 金额:
    $ 15.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

SOCS1 is a crucial regulator for uveal melanoma response to immunotherapy PROJECT SUMMARY/ABSTRACT Targeted and immune therapies generated remarkable clinical responses in cutaneous melanoma (CM) patients. However, uveal melanoma (UM) is among those cancer types that have benefited little or not at all from targeted therapy or immune checkpoint inhibitors (CPIs). Currently, there is no FDA-approved systemic therapy for patients with metastatic UM. The mechanism underlying poor response to CPIs in UM is unclear. There is an urgent need to develop effective prognostic markers and immunotherapies for UM patients. To characterize the immunosuppressive mechanisms in UM, we initiated a study of immune profiling UM tumors derived from patients treated with CPIs. Our preliminary data showed that the suppressor of cytokine signaling 1 (SOCS1) was significantly higher in pre-treatment tumors of responders than nonresponders. Moreover, SOCS1 is correlated with UM patients′ survival and most major histocompatibility complex (MHC) molecules′ expressions. SOCS1 is a known prominent regulator of cytokine signaling and tumor microenvironment. To date, a major gap lies in our understanding of the functional role of SOCS1 in UM. Herein, we hypothesize that SOCS1 is a crucial factor regulating the immune infiltrates and tumor immunogenicity of UM via promoting MHC molecules’ expression. Markedly, the suppression of SOCS1 underlies the poor response to immune CPIs in UM, and upregulation of SOCS1 in tumors can overcome this drug resistance. Thus, we propose the following specific aims of preclinical translational research to investigate the role of SOCS1 in immune-silent UM tumors. Aim 1) To characterize the SOCS1-associated immune signature of UM that correlates with the patient's clinical response to immune CPIs. Aim 2) To investigate the epigenetic and transcriptional mechanisms suppressing SOCS1 and MHC expressions in immune cold UM cells. Aim 3) To enhance the immune response in UM tumors by SOCS1 modulators and further examine their antitumor effects in combination with CPIs. In this project, the levels and function of various immune infiltrates related to SOCS1 will be profiled in UM tumors. We will identify a distinct SOCS1-associated immune signature that can be a predictive marker for UM patient’s response to CPIs and overall survival. Moreover, by unveiling the signaling pathways or factors suppressing SOCS1 and MHC expressions in UM, we expect to identify novel drug targets to upregulate the expressions of these genes, which will convert an immune cold into a hot tumor. For the first time, we will investigate a novel strategy to combine small modulators that can upregulate SOCS1 expression with CPIs to enhance the anticancer immunity of cytotoxic T cells against UM tumors. The proposed studies are expected to produce data to address one unmet need for developing effective targeted and immune therapies for UM. This project has great translational potential and long-term applicability to other forms of cancers, such as immune-resistant CM, head and neck cancer, breast cancer, and liver cancer, in which SOCS1 is known to be significantly correlated with patients' overall survival.
SOCS 1是葡萄膜黑色素瘤对免疫治疗反应的关键调节因子 项目摘要/摘要 靶向和免疫治疗在皮肤黑色素瘤(CM)患者中产生了显著的临床反应。 然而,葡萄膜黑色素瘤(UM)是那些从靶向治疗中受益很少或根本没有受益的癌症类型之一。 免疫检查点抑制剂(CPI)。目前,没有FDA批准的全身治疗用于 转移性UM患者。UM患者对CPI反应不良的机制尚不清楚。有一个 迫切需要开发有效的预后标记物和免疫治疗UM患者。表征 在UM的免疫抑制机制,我们开始了免疫分析UM肿瘤的研究, 接受CPI治疗的患者。我们的初步数据表明,细胞因子信号转导抑制因子1(SOCS 1) 在治疗前肿瘤的应答者中显著高于无应答者。此外,SOCS 1是 与UM患者的生存率和大多数主要组织相容性复合体(MHC)分子的表达相关。 SOCS 1是已知的细胞因子信号传导和肿瘤微环境的显著调节剂。迄今为止, 在于我们对SOCS 1在UM中的功能作用的理解。在此,我们假设SOCS 1是一个关键的 通过促进MHC分子表达调节UM免疫浸润和肿瘤免疫原性的因子 表情明显地,SOCS 1的抑制是UM中对免疫CPI的不良反应的基础,并且 肿瘤中SOCS 1的上调可以克服这种耐药性。因此,我们提出以下具体建议: 临床前转化研究的目的是研究SOCS 1在免疫沉默UM肿瘤中的作用。目标1) 表征与患者临床症状相关的UM SOCS 1相关免疫特征, 对免疫CPI的反应。目的2)探讨抑制细胞凋亡的表观遗传和转录机制。 SOCS 1和MHC在免疫冷UM细胞中的表达。目的3)增强UM肿瘤的免疫应答 通过SOCS 1调节剂,并进一步检查其与CPI组合的抗肿瘤作用。本工程 与SOCS 1相关的各种免疫浸润物的水平和功能将在UM肿瘤中进行分析。我们将确定 一种独特的SOCS 1相关免疫特征,可以作为UM患者对 CPI和总体生存率。此外,通过揭示信号通路或抑制SOCS 1的因子, UM中的MHC表达,我们期望确定新的药物靶点来上调这些基因的表达, 它会将免疫感冒转化为热肿瘤。这是第一次,我们将研究一种新的策略, 联合收割机可上调SOCS 1表达的小调节剂与CPI结合,以增强抗癌免疫力 细胞毒性T细胞对抗UM肿瘤。拟议的研究预计将产生数据,以解决一个 开发针对UM的有效靶向和免疫疗法的未满足需求。这个项目有很大的翻译 潜在的和长期的适用性,以其他形式的癌症,如免疫耐药CM,头部和颈部 癌症、乳腺癌和肝癌,其中已知SOCS 1与患者的 总体生存率。

项目成果

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