Negative regulation of myeloid-derived suppressive cells in cancer

髓系细胞是肿瘤微环境的重要组成部分。髓系细胞分化异常 现在被认为是癌症的主要免疫学标志。世界上最显著的变化之一 在癌症中，髓系室是病理上激活的相对不成熟的髓系的扩张。 具有抑制免疫反应能力的细胞--髓系来源的抑制细胞(MDSC)。 近年来，MDSC成为抑制抗癌免疫和 限制癌症免疫治疗的疗效。因此，对调控机制的理解 MDSC功能具有基础性和翻译上的重要性。因为只有一小部分单核细胞 和中性粒细胞获得MDSC的特征，具体机制尚不清楚 负责这样的转换。在MDSC中发现了丰富的免疫抑制机制 也提出了一个问题，为什么这些细胞在癌症中的积累没有导致深刻的全球 对宿主的免疫抑制。我们在知识上的这种差距阻碍了针对MDSC的进展 功能，以提高免疫疗法的疗效。我们新的初步数据表明， 干扰素(IFN1)信号在防止免疫获得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限制MDSC的抑制活性。全 干扰素1(包括干扰素-α和干扰素-β)通过与由两条链组成的表面受体结合来传递信号 (IFNAR1/2)。根据我们的初步数据，我们假设IFN1是在炎症或 癌症干扰MDSC获得免疫抑制活性。在急性病毒感染和 细菌感染这一机制通过以下方式防止免疫抑制活动的发展 中性粒细胞和单核细胞，否则会影响免疫反应。然而，在癌症方面， 由于肿瘤诱导IFNAR1的下调，这种机制是有限的。因此，IFN1为负值 MDSC中的信号被阻断，这些细胞可以显示出强大的抑制活动，从而限制了这种作用 癌症免疫疗法的最新进展。因此，靶向下调MDSC中IFNAR1的表达可能有价值 治疗效果。这项提案的总体目标是确定生物和生化机制 负性调节MDSC的免疫抑制活性及其治疗方法的研究 监管。

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.