Berges Carsten, Chatterjee Manik, Topp Max S, Einsele Hermann
Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany.
Immunol Res. 2016 Jun;64(3):687-98. doi: 10.1007/s12026-015-8778-2.
Acute graft-versus-host disease (aGvHD) is still a major cause of transplant-related mortality after allogeneic stem cell transplantation (ASCT). It requires immunosuppressive treatments that broadly abrogate T cell responses including beneficial ones directed against tumor cells or infective pathogens. Polo-like kinase 1 (PLK1) is overexpressed in many cancer types including leukemia, and clinical studies demonstrated that targeting PLK1 using selective PLK1 inhibitors resulted in inhibition of proliferation and induction of apoptosis predominantly in tumor cells, supporting the feasibility of PLK1 as target for anticancer therapy. Here, we show that activation of alloreactive T cells (Tallo) up-regulate expression of PLK1, suggesting that PLK1 is a potential new candidate for dual therapy of aGvHD and leukemia after ASCT. Inhibition of PLK1, using PLK1-specific inhibitor GSK461364A selectively depletes Tallo by preventing activation and by inducing apoptosis in already activated Tallo, while memory T cells are preserved. Activated Tallo cells which survive exposure to PLK1 undergo inhibition of proliferation by induction of G2/M cell cycle arrest, which is accompanied by accumulation of cell cycle regulator proteins p21(WAF/CIP1), p27(Kip1), p53 and cyclin B1, whereas abundance of CDK4 decreased. We also show that suppressive effects of PLK1 inhibition on Tallo were synergistically enhanced by concomitant inhibition of molecular chaperone Hsp90. Taken together, our data suggest that PLK1 inhibition represents a reasonable dual strategy to suppress residual tumor growth and efficiently deplete Tallo, and thus provide a rationale to selectively prevent and treat aGvHD.
急性移植物抗宿主病（aGvHD）仍然是异基因干细胞移植（ASCT）后移植相关死亡的主要原因。它需要免疫抑制治疗，这种治疗会广泛消除T细胞反应，包括针对肿瘤细胞或感染性病原体的有益反应。Polo样激酶1（PLK1）在包括白血病在内的多种癌症类型中过度表达，临床研究表明，使用选择性PLK1抑制剂靶向PLK1主要导致肿瘤细胞增殖受到抑制并诱导其凋亡，这支持了将PLK1作为抗癌治疗靶点的可行性。在此，我们表明同种异体反应性T细胞（Tallo）的激活会上调PLK1的表达，这表明PLK1是ASCT后aGvHD和白血病双重治疗的潜在新候选药物。使用PLK1特异性抑制剂GSK461364A抑制PLK1，通过阻止激活并诱导已激活的Tallo凋亡，选择性地消耗Tallo，同时保留记忆T细胞。在暴露于PLK1后存活的激活Tallo细胞通过诱导G2/M期细胞周期停滞而增殖受到抑制，这伴随着细胞周期调节蛋白p21（WAF/CIP1）、p27（Kip1）、p53和细胞周期蛋白B1的积累，而CDK4的丰度降低。我们还表明，分子伴侣Hsp90的同时抑制可协同增强PLK1抑制对Tallo的抑制作用。综上所述，我们的数据表明，抑制PLK1是一种合理的双重策略，可抑制残留肿瘤生长并有效消耗Tallo，从而为选择性预防和治疗aGvHD提供了理论依据。
