In a search by Deng et al. for co-inhibitory or costimulatory domains related to survival in AML, leukocyte immunoglobulin and co-inhibitory receptor B4 (LILRB4), a molecule known to inhibit T cell activity, emerged. LILRB4 expression is restricted to monocytes and subsets of AML. In vitro experiments with LILRB4-/- AML cells or antibody blockade of LILRB4 demonstrated enhanced T cell proliferation and cytotoxicity and decreased AML migration. Multiple in vivo models confirmed improved tumor control. Mechanistically, LILRB4 signaling in AML cells occured through SHP2/NFκB and upregulated uPAR/ARG1 to suppress T cells.
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia(1). 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.
Author Info: (1) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (2) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine,
Author Info: (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) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (6) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China. (7) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medical and Life Science, Wenzhou Medical University, Wenzhou, China. (8) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. School of Public Health, Xiamen University, Xiamen, China. (9) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (10) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Immunology, Xiangya Medical School, Central South University, Changsha, China. (11) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Institute of Biomedical Sciences and the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. (12) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China. (13) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (14) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. (15) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (16) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (17) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. Xiangya Medical School, Central South University, Changsha, China. (18) Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. (19) Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan. (20) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (21) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (22) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen, China. (23) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. (24) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. (25) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (26) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (27) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Xiangya Medical School, Central South University, Changsha, China. (28) Immune-Onc Therapeutics, Inc., Palo Alto, CA, USA. (29) Department of Immunology, Xiangya Medical School, Central South University, Changsha, China. (30) Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (31) Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. (32) Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan. (33) School of Public Health, Xiamen University, Xiamen, China. (34) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (35) Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. (36) Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. (38) Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. (39) Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. (40) Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (41) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (42) Immune-Onc Therapeutics, Inc., Palo Alto, CA, USA. (43) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. zhiqiang.an@uth.tmc.edu. (44) Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhengjunke@sjtu.edu.cn. (45) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. ningyan.zhang@uth.tmc.edu. (46) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. alec.zhang@utsouthwestern.edu.
