Modulation of T cell metabolism to restore immune cell effector functions against high-grade serous ovarian cancer

卵巢癌是第二大致命的妇科恶性肿瘤，在德国每年估计有7000例新病例和约5400人死亡。高级别浆液性卵巢癌(HGSOC)是最常见和最致命的亚型。尽管有新的治疗方法，但HGSOC患者的总体存活率在过去十年中只有轻微的改善。HGSOC中大量浸润性T细胞与患者预后的改善相关。这表明T细胞在卵巢癌的临床过程中起着关键作用。然而，免疫疗法，如免疫检查点抑制剂，在治疗HGSOC方面只显示出温和的效果，尽管随后T细胞被激活。为什么这些有希望的疗法在治疗上没有成功，目前还不清楚。然而，各种研究表明，肿瘤微环境(TME)的代谢影响，如葡萄糖的缺乏，代谢副产物的释放，如乳酸，可以抑制T细胞效应功能。脂肪细胞被证明在肿瘤进展中发挥重要作用，为肿瘤细胞提供能量和信号脂质。T细胞功能的丧失和脂肪细胞之间的联系被证明，这可能是由于代谢调节。然而，脂肪细胞和HGSOC细胞如何调节T细胞代谢，以及这些改变的代谢途径如何降低抗肿瘤免疫功能尚不清楚。本项目的目的是研究HGSOC TME中浸润性T细胞的特征，并探讨HGSOC细胞和脂肪细胞对T细胞代谢和效应器功能的影响。为了实现这些目标，将采用创新的方法，如飞行时间质谱仪和代谢组学，以详细描述免疫细胞和细胞新陈代谢。此外，器官型3D培养将能够研究肿瘤细胞、脂肪细胞和T细胞之间的相互影响，以检测抑制抗肿瘤反应的机制。抑制代谢机制的调节可以恢复T细胞的功能，为卵巢癌的创新和有效治疗方法的发展提供必要的信息。

Ovarian cancer is the second deadliest gynecological malignancy with an estimated 7000 new cases and about 5400 deaths each year in Germany. High-grade serous ovarian cancer (HGSOC) is the most common and deadliest subtype. Despite new therapeutic approaches, the overall survival of patients with HGSOC has only slightly improved in the last decades.High numbers of infiltrating T cells in HGSOC correlate with improved patient outcome. This indicates that T cells play pivotal roles in the clinical course of ovarian cancer. However, immune therapies, such as immune checkpoint inhibitors, only showed modest results in the treatment of HGSOC, despite subsequent T cell activation. Why these promising therapies have not been therapeutically successful, remains unclear. However, a variety of studies were able to demonstrate that metabolic influences of the tumor microenvironment (TME), such as deprivation of glucose, and discharge of metabolic byproducts, such as lactate, can inhibit T cell effector functions.Adipocytes were shown to play an essential role in tumor progression by providing tumor cells with energy and signaling lipids. A connection between the loss of T cell functions and adipocytes was demonstrated, which is presumably due to metabolic modulation. However, it is uncertain how adipocytes and HGSOC cells modulate T cell metabolism and how these altered metabolic pathways decrease anti-tumor immunity.The objectives of the proposed project are to characterize infiltrating T cells in the TME of HGSOC and to investigate influences between HGSOC cells and adipocytes on T cell metabolism and effector functions. In order to achieve these objectives, innovative methods such as mass cytometry by time-of-flight and metabolomics will be applied which allow a detailed characterization of immune cells and cell metabolism. Furthermore, an organotypic 3D culture will enable the study of reciprocal influences between tumor cells, adipocytes, and T cells to detect mechanisms that inhibit anti-tumor responses. The modulation of inhibitory metabolic mechanisms could restore the function of T cells and provide essential information for the development of innovative and efficacious therapeutic approaches to ovarian cancer.