Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Int J Oncol. 2017 May;50(5):1810-1820. doi: 10.3892/ijo.2017.3934. Epub 2017 Mar 24.
Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7. We revealed that in a time-dependent manner HCQ induced the expression of NKG2D ligand ULBP4 on the surface of CML cells. This marks the leukemia cell for recognition by Vγ9Vδ2 T cells. Blocking the interaction of NKG2D with its ligands deleted the sensitizing effects of HCQ. In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane. Our results uncovered a previously unknown mechanism for HCQ in CML treatment that underlines the ability of HCQ to modulate the immune visibility of CML cells, and pave the way to the development of new combination treatments with HCQ and Vγ9Vδ2 T cells.
羟氯喹（HCQ）是唯一在临床上使用的自噬抑制剂，它在治疗慢性髓系白血病（CML）方面显示出巨大的潜力。通过抑制自噬，HCQ 增强了化疗对 CML 的疗效。在本研究中，我们证明 HCQ 可使 CML 细胞对 Vγ9Vδ2 T 细胞介导的裂解敏感。HCQ 抑制 CML 细胞中的自噬，但 HCQ 的敏化作用是不依赖于自噬的。由于 ATG7 敲低不能模拟敏化作用，甚至在没有 ATG7 的情况下也会发生。我们揭示了 HCQ 以时间依赖性方式诱导 CML 细胞表面 NKG2D 配体 ULBP4 的表达。这标志着白血病细胞被 Vγ9Vδ2 T 细胞识别。阻断 NKG2D 与其配体的相互作用会消除 HCQ 的敏化作用。此外，我们表明 HCQ 不影响 ULBP4 的合成或降解，但诱导 ULBP4 从细胞质易位到细胞膜。我们的研究结果揭示了 HCQ 在 CML 治疗中的一个先前未知的机制，强调了 HCQ 调节 CML 细胞免疫可见性的能力，并为 HCQ 与 Vγ9Vδ2 T 细胞联合治疗的开发铺平了道路。
