Regulation of NK cells through extracellular vesicles and microbiota released metabolites in PDAC

通过 PDAC 中的细胞外囊泡和微生物群释放的代谢物调节 NK 细胞

• 批准号: 391345463
• 负责人: Professorin Dr. Elke Pogge von Strandmann
• 金额: --
• 依托单位: Zentrum für Tumor- und Immunbiologie (ZTI)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/391345463?language=en
• 关键词: Regulation; NK; cells; through; extracellular

The critical role of NK cells in tumor immunosurveillance is widely accepted, but the tumor-dependent suppression of NK cell activity in PDAC and consequently NK cell-based immunotherapies are relatively underexplored. Within the first funding period we investigated the biogenesis of extracellular vesicles released by tumor cells and their impact on NK cell functions. We established that EV biogenesis depends on the activity of the chaperone/NK cell-ligand NKp30 via the CBP/p300/p53 axis. Frequent dysfunction of this pathway due to P53 mutations leads to the release of EVs with specific cargo loading associated with reported pro-tumorigenic activity in PDAC (MIF, glypican-1) and factors (actin-binding proteins, MyHII) that were so far not described in PDAC-EVs. These EVs inhibited NK cell cytotoxicity and instead promoted an exhaustion phenotype in NK cells from healthy donors. Based on this data we will dissect EV-mediated in vivo mechanisms, which reprogram NK cells within the immune suppressive and tumor-promoting PDAC-microenvironment (TME) using a Pan02-transplantation model. The phenotype and the activity of tumor associated NK cells (TANK) will be analyzed in detail and the potential of identified EV-associated factors as biomarkers will be analyzed. Expected results will be validated in human samples. Recently, the crucial role of intestinal and intratumoral bacteria for the anti-tumor immune responses in PDAC was reported. Preliminary own data suggest that short chain fatty acids (SCFAs) and bacterial vesicles released by the microbiota impair NK cell activity. Thus the cross-talk of SCFAs and EVs in regulating NK cells will be analyzed. Perpectively, the data obtained will be used to design therapeutic EVs which are able to overcome NK cell-inhibition and instead stimulate NK cell activity to improve NK cell-based immunotherapies for PDAC.

NK细胞在肿瘤免疫监测中的关键作用被广泛接受，但是肿瘤依赖于PDAC中NK细胞活性的抑制作用，因此基于NK细胞的免疫疗法相对尚未得到相对泛滥。在第一个资金期间，我们研究了肿瘤细胞释放的细胞外囊泡的生物发生及其对NK细胞功能的影响。我们确定EV生物发生取决于通过CBP/p300/p53轴伴侣/NK细胞配体NKP30的活性。由于p53突变引起的该途径的频繁功能障碍导致电动汽车释放，而在PDAC（MIF，Glypican-1）中与报道的促肿瘤活性相关的特定货物载荷释放，而迄今为止的因子（肌动蛋白结合蛋白，MYHII）在PDAC-EV中进行了描述。这些电动汽车抑制了NK细胞细胞毒性，而是促进了来自健康供体的NK细胞中的精疲力尽表型。基于这些数据，我们将使用PAN02-移植模型在免疫抑制和促进肿瘤的PDAC微环境（TME）中进行重新编程的体内机制。将详细分析肿瘤相关NK细胞（储罐）的表型和活性，并分析已鉴定的EV相关因子的潜力。预期结果将在人类样品中得到验证。最近，据报道，肠内和肿瘤内细菌在PDAC中抗肿瘤免疫反应的关键作用。初步的自身数据表明，小链脂肪酸（SCFA）和微生物群释放的细菌囊泡会损害NK细胞活性。因此，将分析调节NK细胞中SCFA和EV的串扰。宜人的数据，获得的数据将用于设计能够克服NK细胞抑制的治疗性EV，而是刺激NK细胞活性以改善基于NK细胞的PDAC免疫疗法。