Bialek Joanna, Yankulov Stefan, Kawan Felix, Fornara Paolo, Theil Gerit
Medical Faculty, Clinic of Urology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
Biomedicines. 2022 Dec 13;10(12):3244. doi: 10.3390/biomedicines10123244.
The expression and cellular mechanisms of programmed cell death-1 protein (PD-1) and its ligands (PD-L1 and PD-L2) in renal cancer cells are not well known. Here, we aimed to investigate the response of renal carcinoma subtypes to the immune checkpoint inhibitor nivolumab and its impact on related signaling pathways. All cell lines analyzed (clear cell (cc)RCC (Caki-1, RCC31) and papillary (p)RCC (ACHN, RCC30)) expressed PD-1 and both ccRCC cell lines, and RCC30 expressed PD-L1. Nivolumab treatment at increasing doses led to increased PD-1 levels in analyzed cells and resulted in aggressive behavior of pRCC but diminished this behavior in ccRCC. The analysis of PD-1/PD-L1-associated signaling pathways demonstrated increased AKT activity in Caki-1 and RCC30 cells but decreased activity in ACHN and RCC31 cells, while ribosomal protein S6 remained largely unchanged. Androgen receptors are related to RCC and were predominantly increased in RCC30 cells, which were the only cells that formed nivolumab-dependent spheroids. Finally, all cell lines exhibited a complex response to nivolumab treatment. Since the pRCC cells responded with increased tumorigenicity and PD-1/PD-L1 levels while ccRCC tumorigenicity was diminished, further studies are needed to improve nivolumab-based therapy for renal carcinoma subtypes, especially the identification of response-involved molecular pathways.
程序性细胞死亡蛋白1（PD-1）及其配体（PD-L1和PD-L2）在肾癌细胞中的表达及细胞机制尚不清楚。在此，我们旨在研究肾癌亚型对免疫检查点抑制剂纳武单抗的反应及其对相关信号通路的影响。所有分析的细胞系（透明细胞（cc）RCC（Caki-1、RCC31）和乳头状（p）RCC（ACHN、RCC30））均表达PD-1，且两个ccRCC细胞系以及RCC30均表达PD-L1。增加剂量的纳武单抗处理导致分析细胞中PD-1水平升高，并导致pRCC出现侵袭性行为，但在ccRCC中这种行为减弱。对PD-1/PD-L1相关信号通路的分析表明，Caki-1和RCC30细胞中AKT活性增加，而ACHN和RCC31细胞中活性降低，而核糖体蛋白S6基本保持不变。雄激素受体与RCC相关，在RCC30细胞中主要增加，RCC30是唯一形成纳武单抗依赖性球体的细胞。最后，所有细胞系对纳武单抗处理均表现出复杂的反应。由于pRCC细胞的致瘤性和PD-1/PD-L1水平增加，而ccRCC的致瘤性减弱，因此需要进一步研究以改善基于纳武单抗的肾癌亚型治疗，尤其是识别涉及反应的分子途径。
