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

Nature. 2018 Oct;562(7728):605-609. doi: 10.1038/s41586-018-0615-z.

Mi Deng ¹, Xun Gui ², Jaehyup Kim ³, Li Xie ⁴, Weina Chen ³, Zunling Li ¹ ⁵, Licai He ¹ ⁶, Yuanzhi Chen ² ⁷, Heyu Chen ¹, Weiguang Luo ¹ ⁸, Zhigang Lu ¹ ⁹, Jingjing Xie ¹ ⁵, Hywyn Churchill ³, Yixiang Xu ², Zhan Zhou ¹, Guojin Wu ¹, Chenyi Yu ² ¹⁰, Samuel John ¹¹, Kouyuki Hirayasu ¹², Nam Nguyen ¹, Xiaoye Liu ¹, Fangfang Huang ¹ ¹³, Leike Li ², Hui Deng ², Haidong Tang ³, Ali H Sadek ¹, Lingbo Zhang ¹ ¹⁰, Tao Huang ¹⁴, Yizhou Zou ⁸, Benjamin Chen ¹⁵, Hong Zhu ¹⁶ ¹⁷, Hisashi Arase ¹², Ningshao Xia ⁷, Youxing Jiang ¹, Robert Collins ¹⁸, M James You ¹⁹, Jade Homsi ¹⁸, Nisha Unni ¹⁸, Cheryl Lewis ¹⁷, Guo-Qiang Chen ⁴, Yang-Xin Fu ³, X Charlene Liao ¹⁴, Zhiqiang An ²⁰, Junke Zheng ²¹, Ningyan Zhang ²², Cheng Cheng Zhang ²³

Affiliations

1 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5 Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China.
6 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medical and Life Science, Wenzhou Medical University, Wenzhou, China.
7 School of Public Health, Xiamen University, Xiamen, China.
8 Department of Immunology, Xiangya Medical School, Central South University, Changsha, China.
9 Institute of Biomedical Sciences and the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
10 Xiangya Medical School, Central South University, Changsha, China.
11 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
12 Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
13 Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen, China.
14 Immune-Onc Therapeutics, Inc., Palo Alto, CA, USA.
15 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
16 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
17 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
18 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
19 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
20 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. [email protected].
21 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
22 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. [email protected].
23 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].

PMID: 30333625 DOI: 10.1038/s41586-018-0615-z

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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