Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vγ9Vδ2 T cell-mediated lysis independent of autophagy.
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.
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Biqing
B
Han
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Yanmin
Y
Zhao
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Yu
Y
Lin
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Shan
S
Fu
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Limengmeng
L
Wang
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Mingming
M
Zhang
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Ruxiu
R
Tie
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Binsheng
B
Wang
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Yi
Y
Luo
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Lizhen
L
Liu
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
Jian
J
Yu
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
He
H
Huang
D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7 / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002462:Cell Membrane / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C488760:RAET1E protein, human; D006886:Hydroxychloroquine; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7