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 细胞在肿瘤免疫监视中的关键作用已被广泛接受，但 PDAC 中 NK 细胞活性的肿瘤依赖性抑制以及基于 NK 细胞的免疫疗法的研究相对较少。在第一个资助期内，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 生物发生取决于分子伴侣/NK 细胞配体 NKp30 通过 CBP/p300/p53 轴的活性。由于 P53 突变，该通路频繁发生功能障碍，导致 EV 释放，其具有与 PDAC 中报道的促肿瘤活性（MIF、磷脂酰肌醇蛋白聚糖-1）和迄今为止在 PDAC-EV 中尚未描述的因子（肌动蛋白结合蛋白，MyHII）相关的特定货物负载。这些 EV 抑制 NK 细胞的细胞毒性，反而促进健康供体的 NK 细胞出现耗竭表型。基于这些数据，我们将剖析 EV 介导的体内机制，该机制使用 Pan02 移植模型在免疫抑制和肿瘤促进 PDAC 微环境 (TME) 中重新编程 NK 细胞。将详细分析肿瘤相关 NK 细胞 (TANK) 的表型和活性，并分析已确定的 EV 相关因子作为生物标志物的潜力。预期结果将在人体样本中得到验证。最近，报道了肠道和瘤内细菌对于 PDAC 抗肿瘤免疫反应的关键作用。初步数据表明，微生物群释放的短链脂肪酸 (SCFA) 和细菌囊泡会损害 NK 细胞活性。因此，将分析 SCFA 和 EV 在调节 NK 细胞中的串扰。从长远来看，获得的数据将用于设计治疗性 EV，这些 EV 能够克服 NK 细胞抑制，并刺激 NK 细胞活性，从而改善基于 NK 细胞的 PDAC 免疫疗法。