Stress Pathways in Tumors Drive Global MDSC Activity and Survival through Chop

描述(申请人提供)：髓系来源的抑制细胞(MDSC)在荷瘤宿主体内积聚是抑制T和NK细胞反应的重要机制，也是免疫治疗的主要障碍。MDSC的抑制活性被归因于几个途径，包括氨基酸精氨酸和半胱氨酸的耗尽；活性氧物种、过氧亚硝酸盐和前列腺素E2的释放；以及调节性T细胞的诱导。不幸的是，对MDSC诱导的免疫抑制机制的了解尚未转化为全球阻断癌症MDSC功能的成功疗法。我们假设，对中枢调节因子的识别和抑制 肿瘤中的MDSC免疫调节活性将克服T细胞的抑制，并提高基于T细胞的免疫疗法的疗效。在这项研究中，我们旨在确定C/EBP同源应激相关蛋白(CHOP)作为MDSC免疫抑制活性的主要调节因子的作用。CHOP是一种常见的应激传感器，通常与诱导细胞凋亡有关。我们假设MDSC中CHOP的诱导是由多种应激相关因素共同驱动MDSC抑制T细胞反应和调节MDSC周转/存活内稳态的能力。因此，抑制CHOP或其上游介质在肿瘤中的治疗作用将阻断MDSC的功能，恢复保护性的抗肿瘤效应T细胞应答，提高T细胞免疫治疗的疗效。这一假说是基于我们广泛的初步发现，表明CHOP在MDSC活动中起核心作用。我们将通过以下具体目的来验证我们的假设并实现本研究的目的：(1)确定CHOP在间质中的表达调节免疫抑制活性和肿瘤中MDSC积累的机制。(2)探讨肿瘤浸润性MDSC诱导CHOP表达的机制。(3)验证药物抑制或CHOP基因缺失将阻断MDSC功能和提高T细胞免疫治疗癌症疗效的预测。这项拟议研究的完成将首次描述肿瘤中的多种应激因素如何通过一种独特的途径驱动全球MDSC活动。此外，这些结果将有助于表征和开发一种新的治疗方法，该方法具有阻断MDSC的全局免疫抑制功能并恢复癌症保护性T细胞免疫的潜力。此外，这项建议中建立的方法学也可以应用于MDSC是T细胞抑制的主要媒介的其他疾病。

DESCRIPTION (provided by applicant): Accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is an important mechanism of suppression of T and NK cell responses and a major obstacle to immunotherapy. MDSC inhibitory activity has been attributed to several pathways, including the depletion of the amino acids arginine and cysteine; the release of reactive oxygen species, peroxynitrites, and prostaglandin E2; and the induction of regulatory T cells. Unfortunately, the understanding of the immune-inhibitory mechanisms induced by MDSC has not yet been translated into successful therapies to globally block MDSC function in cancer. We postulate that the identification and inhibition of the central mediators of MDSC-immune regulatory activity in tumors will overcome T cell suppression and increase the efficacy of T cell-based immunotherapies. In this proposal, we aim to determine the role of the C/EBP homologous stress-related protein (Chop), a common stress sensor usually associated with the induction of cellular apoptosis, as a master regulator of the immune suppressive activity of MDSC. We hypothesize that the induction of Chop in MDSC by multiple stress-related factors, globally drives the ability of MDSC to inhibit T cell responses and modulates MDSC turnover/survival homeostasis. Therefore, therapeutic inhibition of Chop or its upstream mediators in tumors will block MDSC function, restore protective anti-tumor effector T cell responses, and increase the efficacy of T cell-based immunotherapies. This hypothesis is based upon our extensive preliminary findings suggesting the central role of Chop on MDSC activity. We will test our hypothesis and achieve the objectives of this study through the following Specific Aims: (1) To determine the mechanisms by which the expression of Chop in the stroma regulates the immune suppression activity and the accumulation of MDSC in tumors. (2) To determine the mechanisms that induce Chop expression in tumor-infiltrating MDSC. (3) To test the prediction that pharmacological inhibition or genetic deletion of Chop will block MDSC function and increase the efficacy of T cell-based immunotherapies in cancer. Completion of the proposed study will describe for the first time how multiple stress factors in tumors drive global MDSC activity through a unique pathway. In addition, the results will help characterize and develop a novel therapeutic approach, which carries the potential to block the global immune inhibitory functions of MDSC and to restore protective T cell immunity in cancer. Moreover, the methodology established in this proposal could be applied into other diseases where MDSC are major mediators of T cell suppression.