Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy
Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy
复制标题
羟氯喹使慢性粒细胞白血病细胞对 Vγ9Vγ2 T 细胞介导的裂解敏感，与自噬无关
DOI：
10.3892/ijo.2017.3934
复制
发表时间：
2017-05-01
影响因子：
5.2
通讯作者：
Huang, He
中科院分区：
文献类型：
--
作者：
Han, Biqing;Zhao, Yanmin;Huang, He
羟氯喹（HCQ）是目前临床应用中唯一的自噬抑制剂，在治疗慢性髓系白血病（CML）方面展现出巨大潜力。通过抑制自噬，羟氯喹提高了化疗对慢性髓系白血病的治疗效果。在本研究中，我们证实羟氯喹可使慢性髓系白血病细胞对Vγ9Vδ2 T细胞介导的裂解作用更加敏感。羟氯喹抑制了慢性髓系白血病细胞的自噬，但羟氯喹的这种致敏作用与自噬无关。因为敲低ATG7基因无法模拟出这种致敏效果，甚至在ATG7基因缺失的情况下该致敏作用依然存在。我们发现，羟氯喹能以时间依赖的方式诱导慢性髓系白血病细胞表面NKG2D配体ULBP4的表达。这使得白血病细胞能够被Vγ9Vδ2 T细胞识别。阻断NKG2D与其配体的相互作用，羟氯喹的致敏作用就会消失。此外，我们还表明羟氯喹并不影响ULBP4的合成或降解，而是诱导ULBP4从细胞质转移到细胞膜。我们的研究结果揭示了羟氯喹治疗慢性髓系白血病中一种此前未知的机制，突出了羟氯喹调节慢性髓系白血病细胞免疫可见性的能力，为开发羟氯喹与Vγ9Vδ2 T细胞联合的新型治疗方案铺平了道路。
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 V gamma 9V delta 2 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 V gamma 9V delta 2 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 V gamma 9V delta 2 T cells.