Mechanism of myeloid cell defect in cancer

 描述(申请人提供)：髓系来源的抑制细胞(MDSCs)现在被证实是调节癌症免疫反应的关键因素之一。这些细胞的特点是共同的髓系起源、未成熟状态和免疫抑制活性。与MDSCs表型相同的未成熟髓系细胞(IMC)在健康人的骨髓中不断产生，并分化为成熟的髓系细胞，而不会引起明显的免疫抑制。然而，在癌症中，正常的髓系细胞分化会偏离其固有的成熟巨噬细胞(MF)、树突状细胞(DC)或中性粒细胞(PMN)的终末分化途径，而有利于病理性MDSCs的分化。MDSC的频率与癌症患者的不良预后和进展相关。在一些小鼠肿瘤模型和临床研究中已经证明了肿瘤负荷和MDSC频率之间的直接关系，以及MDSC和外周血中T细胞频率之间的负相关。尽管有大量关于MDSC生物学的信息，但IMC获得免疫抑制活性的原因在很大程度上仍不清楚。缺乏对肿瘤进展过程中IMC向MDSC转化的确切机制的了解，不仅限制了我们对髓系细胞生物学的看法，也限制了我们对这些细胞用于治疗目的的调控的尝试。MDSC的抑制特性将为骨髓移植中移植物抗宿主病(GVHD)的细胞治疗以及许多自身免疫疾病提供独特的机会。然而，在没有使用肿瘤条件培养液的情况下，在体外培养人和小鼠的MDSC仍然是难以实现的。这阻碍了将这种方法应用于临床试验的尝试。我们最近发现，与对照组单核细胞和中性粒细胞相比，人和小鼠的MDSC显示出内质网(ER)应激的迹象。我们认为内质网应激可能在调节这些细胞的免疫抑制功能中起重要作用。在这一应用中，我们计划研究内质网应激在MDSC中的机制和功能后果。我们将探索利用这一新的观察结果在体外产生人和小鼠的MDSC的可能性，用于潜在的临床应用。本研究包括三个具体目的：1.评价肿瘤进展过程中MDSC的内质网应激反应；2.明确内质网应激对MDSC功能的影响机制。具体目的3.明确内质网应激在MDSC中的诱导机制及其可能的治疗作用。

 DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSCs) are now established as one of critical factors regulating immune responses in cancer. These cells are characterized by common myeloid origin, immature state and immune suppressive activity. Immature myeloid cells (IMC) with the same phenotype as MDSCs are continually generated in the bone marrow of healthy individuals and differentiate into mature myeloid cells without causing detectable immunosuppression. However, in cancer, normal myeloid cell differentiation is diverted from its intrinsic pathway of terminal differentiation of mature macrophages (MF), dendritic cells (DCs), or polymorphonuclear neutrophils (PMN) and instead favors differentiation of pathological MDSCs. The frequency of MDSC correlates with a poor prognosis and progression in cancer patients. A direct relationship between tumor burden and MDSC frequency has been demonstrated in several mouse tumor models and clinical studies, as well as, an inverse correlation between MDSC and T-cell frequency in the peripheral blood. Despite wealth of information regarding MDSC biology, what causes IMC to acquire immune suppressive activity remains largely unclear. Lack of understanding of the exact mechanisms responsible to conversion of IMC to MDSC during tumor progression limits not only our view of myeloid cell biology but also attempts in regulation of these cells with therapeutic purposes. Suppressive features of MDSC would present a unique opportunity to use these cells for cell therapy of graft versus host disease (GVHD) in bone marrow transplantation as well as many autoimmune conditions. However, generation of human and mouse MDSC in vitro without the use of tumor conditioned medium remains elusive. This hampers the attempts to bring this approach to clinical trials. We recently have found that human and mouse MDSC, in contrast to control monocytes and PMN, displayed signs of endoplasmic reticulum (ER) stress. We propose that ER stress may play a major role in regulation of immune suppression function of these cells. In this application we plan to investigate the mechanisms and functional consequences of ER stress in MDSC. We will explore the possibility of using this novel observations for generation of human and mouse MDSC in vitro, for potential clinical use. This application include three specific aims: Specific Aim 1. To evaluate of ER stress response in MDSC during tumor progression Specific Aim 2. To determine the mechanisms of ER stress effect on MDSC function. Specific Aim 3. To identify the mechanisms of ER stress induction in MDSC and their possible use for therapeutic purposes.