Understanding suppression of T effector memory cells by mediators of the ovarian carcinoma microenvironment

了解卵巢癌微环境介质对效应 T 记忆细胞的抑制

• 批准号: 431852296
• 负责人: Professorin Dr. Magdalena Huber
• 金额: --
• 依托单位: Zentrum für Tumor- und Immunbiologie (ZTI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/431852296?language=en
• 关键词: Understanding; suppression; effector; memory; cells

Although CD8+ T cells have a beneficial impact on ovarian carcinoma survival, the tumor microenvironment, including the malignancy-associated peritoneal effusion (ascites), suppresses their function by largely unknown mechanisms. We recently identified a specific accumulation of CD8+ T effector memory (TEM) in ascites associated with a prolonged relapse-free survival (RFS) of patients. However, intracellular signaling molecules that are functionally crucial for T cell activation were suppressed by the ovarian carcinoma microenvironment in TEM cells, thereby leading to their dysfunction. The present cooperation project is based on this work and aims to elucidate the mediators, mechanisms and molecular markers of TEM suppression by ovarian carcinoma ascites. Toward this goal we have designed a systematic approach based on a combination of flow cytometric, biochemical, genetic, omics-based and bioinformatic tools. Our work program encompasses three specific objectives. (i) We aim to identify the specific soluble mediators in ascites that impinge on TEM signaling and function, using normal peripheral TEM cells as the experimental system. We will focus on mediators in ascites that are associated with poor RFS and have receptors on TATs. We will seek to identify further candidates by correlating ascites levels of specific mediators with the inhibition of TEM signaling, which already led to the identification of PD-L2 as a candidate. (ii) We plan to delineate the signaling molecules and pathways in primary TEM cells that transduce the inhibitory effect of PD-L2 and other specific mediators in ascites on TEM signaling by transcriptomic and proteomic approaches. We will compare the obtained data with the RNA and protein profiles of TEM cells from ascites with the goal to define clinically relevant diagnostic markers indicative of T cell “fitness” in patients. (iii) Based on this work, we will aim at rescuing TEM function and thus the delineation of novel therapeutically relevant targets, including the knock-down or pharmacological inhibition of negative signal transducers upregulated in response to mediators in ascites.We anticipate that this study will lead to an improved assessment of the functionality of CD8+ T cell in ovarian cancer patients, thereby providing a basis for novel diagnostic and individualized therapeutic approaches.

虽然CD 8 + T细胞对卵巢癌的生存有有益的影响，但肿瘤微环境，包括恶性肿瘤相关的腹腔积液（腹水），通过很大程度上未知的机制抑制了它们的功能。我们最近确定了一个特定的积累的CD 8 + T效应记忆（TEM）在腹水与延长无复发生存期（RFS）的患者。然而，功能上对T细胞活化至关重要的细胞内信号分子被TEM细胞中的卵巢癌微环境抑制，从而导致其功能障碍。本合作项目就是在此基础上开展的，旨在阐明卵巢癌腹水抑制TEM的介质、机制和分子标志物。为了实现这一目标，我们设计了一个系统的方法的基础上相结合的流式细胞仪，生物化学，遗传学，基于组学和生物信息学的工具。我们的工作计划包括三个具体目标。(i)我们的目的是确定特定的可溶性介质在腹水中的TEM信号和功能的冲击，使用正常的外周TEM细胞作为实验系统。我们将重点关注腹水中与RFS差相关的介质，并在TAT上有受体。我们将寻求通过将特异性介质的腹水水平与TEM信号传导的抑制相关联来鉴定进一步的候选物，这已经导致将PD-L2鉴定为候选物。(ii)我们计划通过转录组学和蛋白质组学方法描述原代TEM细胞中的信号分子和途径，以证实腹水中PD-L2和其他特异性介质对TEM信号传导的抑制作用。我们将比较所获得的数据与来自腹水的TEM细胞的RNA和蛋白质谱，目的是定义指示患者中T细胞“适应性”的临床相关诊断标志物。(iii)基于这项工作，我们将致力于拯救TEM功能，从而描绘新的治疗相关靶点，包括敲低或药理学抑制腹水中对介体的应答上调的负信号转导子。我们预计这项研究将改善对卵巢癌患者CD 8 + T细胞功能的评估，从而为新的诊断和个体化治疗方法提供基础。