LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration

Mi Deng, Xun Gui, Jaehyup Kim, Li Xie, Weina Chen, Zunling Li, Licai He, Yuanzhi Chen, Heyu Chen, Weiguang Luo, Zhigang Lu, Jingjing Xie, Hywyn Churchill, Yixiang Xu, Zhan Zhou, Guojin Wu, Chenyi Yu, Samuel John, Kouyuki Hirayasu, Nam NguyenXiaoye Liu, Fangfang Huang, Leike Li, Hui Deng, Haidong Tang, Ali H. Sadek, Lingbo Zhang, Tao Huang, Yizhou Zou, Benjamin Chen, Hong Zhu, Hisashi Arase, Ningshao Xia, Youxing Jiang, Robert Collins, M. James You, Jade Homsi, Nisha Unni, Cheryl Lewis, Guo Qiang Chen, Yang Xin Fu, X. Charlene Liao, Zhiqiang An, Junke Zheng, Ningyan Zhang, Chengcheng Zhang

Research output: Contribution to journalLetter

8 Citations (Scopus)

Abstract

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Original languageEnglish (US)
Pages (from-to)605-609
Number of pages5
JournalNature
Volume562
Issue number7728
DOIs
StatePublished - Oct 25 2018

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Leukemia
T-Lymphocytes
Acute Myeloid Leukemia
Neoplasms
Immunoreceptor Tyrosine-Based Inhibition Motif
Myeloid Cells
Immunosuppressive Agents
Antibodies
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. / Deng, Mi; Gui, Xun; Kim, Jaehyup; Xie, Li; Chen, Weina; Li, Zunling; He, Licai; Chen, Yuanzhi; Chen, Heyu; Luo, Weiguang; Lu, Zhigang; Xie, Jingjing; Churchill, Hywyn; Xu, Yixiang; Zhou, Zhan; Wu, Guojin; Yu, Chenyi; John, Samuel; Hirayasu, Kouyuki; Nguyen, Nam; Liu, Xiaoye; Huang, Fangfang; Li, Leike; Deng, Hui; Tang, Haidong; Sadek, Ali H.; Zhang, Lingbo; Huang, Tao; Zou, Yizhou; Chen, Benjamin; Zhu, Hong; Arase, Hisashi; Xia, Ningshao; Jiang, Youxing; Collins, Robert; You, M. James; Homsi, Jade; Unni, Nisha; Lewis, Cheryl; Chen, Guo Qiang; Fu, Yang Xin; Liao, X. Charlene; An, Zhiqiang; Zheng, Junke; Zhang, Ningyan; Zhang, Chengcheng.

In: Nature, Vol. 562, No. 7728, 25.10.2018, p. 605-609.

Research output: Contribution to journalLetter

Deng, M, Gui, X, Kim, J, Xie, L, Chen, W, Li, Z, He, L, Chen, Y, Chen, H, Luo, W, Lu, Z, Xie, J, Churchill, H, Xu, Y, Zhou, Z, Wu, G, Yu, C, John, S, Hirayasu, K, Nguyen, N, Liu, X, Huang, F, Li, L, Deng, H, Tang, H, Sadek, AH, Zhang, L, Huang, T, Zou, Y, Chen, B, Zhu, H, Arase, H, Xia, N, Jiang, Y, Collins, R, You, MJ, Homsi, J, Unni, N, Lewis, C, Chen, GQ, Fu, YX, Liao, XC, An, Z, Zheng, J, Zhang, N & Zhang, C 2018, 'LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration', Nature, vol. 562, no. 7728, pp. 605-609. https://doi.org/10.1038/s41586-018-0615-z
Deng, Mi ; Gui, Xun ; Kim, Jaehyup ; Xie, Li ; Chen, Weina ; Li, Zunling ; He, Licai ; Chen, Yuanzhi ; Chen, Heyu ; Luo, Weiguang ; Lu, Zhigang ; Xie, Jingjing ; Churchill, Hywyn ; Xu, Yixiang ; Zhou, Zhan ; Wu, Guojin ; Yu, Chenyi ; John, Samuel ; Hirayasu, Kouyuki ; Nguyen, Nam ; Liu, Xiaoye ; Huang, Fangfang ; Li, Leike ; Deng, Hui ; Tang, Haidong ; Sadek, Ali H. ; Zhang, Lingbo ; Huang, Tao ; Zou, Yizhou ; Chen, Benjamin ; Zhu, Hong ; Arase, Hisashi ; Xia, Ningshao ; Jiang, Youxing ; Collins, Robert ; You, M. James ; Homsi, Jade ; Unni, Nisha ; Lewis, Cheryl ; Chen, Guo Qiang ; Fu, Yang Xin ; Liao, X. Charlene ; An, Zhiqiang ; Zheng, Junke ; Zhang, Ningyan ; Zhang, Chengcheng. / LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. In: Nature. 2018 ; Vol. 562, No. 7728. pp. 605-609.
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abstract = "Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.",
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T1 - LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration

AU - Deng, Mi

AU - Gui, Xun

AU - Kim, Jaehyup

AU - Xie, Li

AU - Chen, Weina

AU - Li, Zunling

AU - He, Licai

AU - Chen, Yuanzhi

AU - Chen, Heyu

AU - Luo, Weiguang

AU - Lu, Zhigang

AU - Xie, Jingjing

AU - Churchill, Hywyn

AU - Xu, Yixiang

AU - Zhou, Zhan

AU - Wu, Guojin

AU - Yu, Chenyi

AU - John, Samuel

AU - Hirayasu, Kouyuki

AU - Nguyen, Nam

AU - Liu, Xiaoye

AU - Huang, Fangfang

AU - Li, Leike

AU - Deng, Hui

AU - Tang, Haidong

AU - Sadek, Ali H.

AU - Zhang, Lingbo

AU - Huang, Tao

AU - Zou, Yizhou

AU - Chen, Benjamin

AU - Zhu, Hong

AU - Arase, Hisashi

AU - Xia, Ningshao

AU - Jiang, Youxing

AU - Collins, Robert

AU - You, M. James

AU - Homsi, Jade

AU - Unni, Nisha

AU - Lewis, Cheryl

AU - Chen, Guo Qiang

AU - Fu, Yang Xin

AU - Liao, X. Charlene

AU - An, Zhiqiang

AU - Zheng, Junke

AU - Zhang, Ningyan

AU - Zhang, Chengcheng

PY - 2018/10/25

Y1 - 2018/10/25

N2 - Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

AB - Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

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U2 - 10.1038/s41586-018-0615-z

DO - 10.1038/s41586-018-0615-z

M3 - Letter

C2 - 30333625

AN - SCOPUS:85055418191

VL - 562

SP - 605

EP - 609

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7728

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