The role of the platelet-leucocyte axis in antiandrogen therapy induced cardiovascular disease

雄激素剥夺疗法（ADT）是前列腺癌局部晚期和转移性疾病治疗的关键因素。ADT与心血管疾病（CVD）相关，包括动脉粥样硬化斑块进展和斑块不稳定。血栓和炎症是动脉粥样硬化和心血管疾病发病的关键机制，血小板活性和血小板-单核细胞相互作用的增加与心血管疾病的风险增加有关。雄激素通路信号对血小板活性和其他动脉粥样硬化相关的细胞类型有无数的影响，这些影响尚不完全清楚。该研究的目的是阐明ADT治疗前列腺癌和心血管疾病之间的机制联系，重点关注血栓炎症和血小板的作用及其与其他免疫细胞的相互作用。本文提出一项纵向队列研究，以综合表征前列腺癌患者ADT前和ADT期间外周血血小板活性、血小板-白细胞相互作用、单核细胞活化、t细胞亚群和血小板转录组。流式细胞术分析将用于表征血小板和白细胞的表型和相互作用。血小板反应性将用光透射聚集法测量。RNA测序将为ADT期间血小板功能提供进一步的机制见解。补充的体外研究将探讨雄激素阻断对巨核细胞活性和表型以及血小板-巨噬细胞相互作用的影响。此外，在这种情况下，不同的抗血小板治疗的效果将在体外研究。确定潜在的治疗靶点或诊断性生物标志物有助于最佳地指导预防措施，从而降低前列腺癌患者接受ADT的过多心血管风险。

Androgen-deprivation therapy (ADT) is a key element of prostate cancer treatment in locally advanced and metastatic disease. ADT is associated with cardiovascular disease (CVD) including atherosclerotic plaque progression and plaque instability. Thrombosis and inflammation are key mechanisms in the pathogenesis of atherosclerosis and CVD and increased platelet activity and platelet-monocyte interaction are associated with an increased risk of CVD. Androgen pathway signaling has a myriad of effects on platelet activity and other atherosclerosis-associated cell types which are incompletely understood. The aim of the proposed study is to elucidate the mechanistic link between ADT for prostate cancer and CVD with a focus on thromboinflammation and the role of platelets and their interaction with other immune cells. A longitudinal cohort study is proposed to comprehensively characterize platelet activity, platelet-leucocyte interaction, monocyte activation, T-cell subsets, and the platelet transcriptome in peripheral blood of prostate cancer patients before and during ADT compared to healthy controls. Flow-cytometric analysis will be used to characterize phenotype and interaction of platelets and leucocytes. Platelet reactivity will be measured using light transmission aggregometry. RNA sequencing will provide further mechanistic insights into platelet function during ADT. Complementary in vitro studies will investigate the effects of androgen-blockade on the megakaryocyte activity and phenotype as well as on platelet-macrophage interaction. Additionally, effects of different antiplatelet therapies in this context will be studied in vitro. The identification of potential therapeutic targets or diagnostic biomarkers could help to optimally guide preventive measures and thereby reduce the excess cardiovascular risk of prostate cancer patients undergoing ADT.