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

卵巢癌是第二致命的妇科恶性肿瘤，估计在德国每年有7000例新发病例和约5400例死亡。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，但在过去的几十年里，HGSOC患者的总体生存率仅略有改善，HGSOC中大量浸润的T细胞与改善的患者预后相关。这表明T细胞在卵巢癌的临床过程中发挥着关键作用。然而，免疫疗法，如免疫检查点抑制剂，在HGSOC的治疗中仅显示出适度的结果，尽管随后的T细胞活化。为什么这些有前途的疗法在治疗上没有成功，目前还不清楚。然而，大量研究表明，肿瘤微环境（TME）的代谢影响，如葡萄糖缺乏和代谢副产物（如乳酸）的释放，可以抑制T细胞效应子功能，脂肪细胞通过为肿瘤细胞提供能量和信号脂质，在肿瘤进展中发挥重要作用。证明了T细胞功能丧失与脂肪细胞之间的联系，这可能是由于代谢调节。然而，它是不确定的脂肪细胞和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immunity.The拟议的项目的目标是表征浸润T细胞在TME的HGSOC和调查HGSOC细胞和脂肪细胞之间的影响T细胞代谢和效应器功能。为了实现这些目标，将应用飞行时间质谱细胞术和代谢组学等创新方法，从而对免疫细胞和细胞代谢进行详细表征。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。调节抑制性代谢机制可以恢复T细胞的功能，并为开发创新和有效的卵巢癌治疗方法提供必要的信息。

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.