SOCS1 is a crucial regulator for uveal melanoma response to immunotherapy

SOCS1是葡萄膜黑色素瘤免疫治疗反应的重要调节因子 项目摘要/摘要 靶向治疗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获益很少或根本没有受益的癌症类型之一 治疗或免疫检查点抑制剂(CPIs)。目前，还没有FDA批准的系统性治疗 转移性UM患者。UM对CPIs反应差的机制尚不清楚。有一个 迫切需要为UM患者开发有效的预后标记物和免疫疗法。要刻画 UM中的免疫抑制机制，我们启动了一项来自UM肿瘤的免疫图谱研究 接受CPIs治疗的患者。我们的初步数据显示，细胞因子信号转导抑制因子1(SOCS1) 在治疗前有反应的肿瘤中显著高于无反应的肿瘤。此外，SOCS1是 与UM患者的生存和大多数主要组织相容性复合体(MHC)分子的表达有关。 SOCS1是已知的细胞因子信号和肿瘤微环境的重要调节因子。到目前为止，一个主要的差距 在于我们对SOCS1在UM中的功能作用的理解。在这里，我们假设SOCS1是一个至关重要的 通过促进MHC分子调节UM免疫浸润和肿瘤免疫原性的因子 表情。值得注意的是，SOCS1的抑制是UM对免疫CPIs反应差的基础，并且 在肿瘤中上调SOCS1可以克服这种耐药性。因此，我们提出以下具体建议 临床前转译研究的目的是研究SOCS1在免疫沉默的UM肿瘤中的作用。目标1) 确定与患者临床相关的UM的SOCS1相关免疫特征 对免疫消费物价指数的反应。目的2)研究表观遗传和转录抑制机制 SOCS1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SOCS1调节剂，并进一步检测其结合CPIs的抗肿瘤作用。在这个项目中， 与SOCS1相关的各种免疫浸润物的水平和功能将在UM肿瘤中得到描述。我们将确定 一种独特的SOCS1相关免疫特征，可作为UM患者对 消费物价指数和总体存活率。此外，通过揭示抑制SOCS1和SOCS1的信号通路或因子 MHC在UM中的表达，我们希望找到新的药物靶点来上调这些基因的表达， 这会将免疫感冒转化为炎热的肿瘤。第一次，我们将研究一种新的策略来 可上调SOCS1表达的小分子调节剂与CPIs结合增强抗癌免疫 抗UM肿瘤的细胞毒性T细胞。预计拟议的研究将产生数据来解决其中一个问题 为UM开发有效的靶向和免疫疗法的需求尚未得到满足。这个项目有很好的翻译能力 潜在和长期适用于其他形式的癌症，如免疫抵抗型CM、头颈部 癌症、乳腺癌和肝癌，已知SOCS1与患者的 总体存活率。

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.