Negative regulation of myeloid-derived suppressive cells in cancer

癌症中骨髓源性抑制细胞的负调控

• 批准号: 10316256
• 负责人: Serge Y Fuchs
• 金额: $ 46.18万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-18 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316256
• 关键词: Acute; Autoimmune Diseases; Bacterial Infections; Binding; Biochemical; Biological; Cell Differentiation process; Cell physiology; Cells; Characteristics; Chronic; Data; Dendritic Cells; Development; Down-Regulation; Family; Goals; Growth Factor; Hematopoietic stem cells; IFNAR1 gene; Immune; Immune response; Immunologics; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Knowledge; Left; Malignant Neoplasms; Methods; Modeling; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Pathologic; Phenotype; Pilot Projects; Regulation; Role; Signal Transduction; Surface; Testing; Therapeutic; Therapeutic Effect; Tumor Immunity; Tumor-associated macrophages; Virus Diseases; acute infection; anti-cancer; base; cancer immunotherapeutics; cancer immunotherapy; cancer therapy; cancer type; cytokine; granulocyte; immune resistance; improved; macrophage; monocyte; neutrophil; prevent; progenitor; receptor; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

Myeloid cells are critical component of tumor microenvironment. Abnormal differentiation of myeloid cells is now considered a major immunological hallmark of cancer. One of the most prominent changes in the myeloid compartment in cancer is the expansion of pathologically activated relatively immature myeloid cells with the potent ability to suppress immune responses – myeloid-derived suppressor cells (MDSC). In recent years, MDSC emerged as critically important regulators that suppress anti-cancer immunity and limit the efficacy of cancer immune therapy. Therefore, understanding of the mechanisms regulating MDSC function is of fundamental and translational importance. As only small proportion of monocytes and neutrophils acquire characteristics of MDSC, it remains unclear which specific mechanisms are responsible for such conversion. An abundance of immune suppressive mechanisms detected in MDSC also raised the question, why accumulation of these cells in cancer, does not result in profound global immune suppression of the host. This gap in our knowledge impedes progress toward targeting MDSC function in order to increase the efficacy of immunotherapies. Our new preliminary data suggest that type 1 interferons (IFN1) signaling have an intrinsic regulatory role in preventing acquisition of the immune suppressive potential by neutrophils and monocytes and in limiting suppressive activity of MDSC. All IFN1 (including IFN-α and IFN-β) signal via binding to a surface receptor composed of two chains (IFNAR1/2). Based on our preliminary data we hypothesize that IFN1 produced during inflammation or cancer interferes with acquisition of immune suppressive activity by MDSC. During acute viral and bacterial infections this mechanism prevents the development of immune suppressive activity by neutrophils and monocytes, which otherwise would compromise immune responses. In cancer, however, this mechanism is limited due to tumor-induced downregulation of IFNAR1. As a result, negative IFN1 signaling in MDSC is blocked and these cells can display potent suppressive activity that limits the effect of cancer immunotherapy. Thus, targeting down-regulation of IFNAR1 in MDSC may have valuable therapeutic effect. Overall goal of this proposal is to identify biological and biochemical mechanisms negatively regulating immune suppressive activity of MDSC and to develop methods of their therapeutic regulation.

髓样细胞是肿瘤微环境的关键成分。髓样细胞异常分化 现在被认为是癌症的主要免疫学标志。最突出的变化之一 癌症中的髓样室是病理活化的相对未成熟髓样的扩展 具有抑制免疫反应的潜在能力的细胞 - 髓样衍生的抑制细胞（MDSC）。 近年来，MDSC成为抑制抗癌免疫力和 限制癌症免疫治疗的效率。因此，了解调节机制 MDSC功能具有基本和转化的重要性。仅一小部分单核细胞 中性粒细胞获得了MDSC的特征，目前尚不清楚哪些特定机制是 负责这种转换。在MDSC中检测到的免疫抑制机制的抽象 还提出了一个问题，为什么这些细胞在癌症中积累，不会导致深刻的全球 免疫抑制宿主。我们知识的这一差距阻碍了针对MDSC的进步 功能以提高免疫疗法的效率。我们的新初步数据表明类型 1个干扰素（IFN1）信号传导在防止获取免疫方面具有内在的调节作用 中性粒细胞和单核细胞的抑制潜力以及MDSC的抑制活性。全部 IFN1（包括IFN-α和IFN-β）信号通过与由两个链组成的表面受体结合 （IFNAR1/2）。根据我们的初步数据，我们假设在炎症期间产生的IFN1或 通过MDSC获得免疫抑制活性，癌症中断。在急性病毒和 细菌感染这种机制可防止通过 中性粒细胞和单核细胞，否则会损害免疫反应。但是，在癌症中 由于肿瘤引起的IFNAR1下调，该机制受到限制。结果，负IFN1 MDSC中的信号传导被阻塞，这些细胞可以显示潜在的抑制活性，从而限制了效果 癌症免疫疗法。那是针对MDSC中IFNAR1下调的目标 治疗效果。该建议的总体目标是确定生物学和生化机制 MDSC的负调控性免疫抑制活性并开发其治疗方法 规定。