Journal Article

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

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

2018

Overview

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. The receptor LILRB4 on monocytic leukaemia cells suppresses T cell activity and support the infiltration of tumour cells into tissues.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 13/51 / 13/95 / 38 / 38/23 / 38/77 / 38/79 / 59 / 631/250/251 / 631/67/580 / 64/60 / 82 / 82/58 / 96 / Acute myelocytic leukemia / Acute myeloid leukemia / Animal models / Animals / Antibodies / Apolipoprotein E / Apolipoproteins / Apolipoproteins E - metabolism / Arginase - metabolism / Bone marrow / Cancer / Cancer treatment / Care and treatment / CD4-Positive T-Lymphocytes - cytology / CD4-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / Cell Movement / Cell Proliferation / Cell receptors / Cells (Biology) / Cellular signal transduction / Clonal deletion / Female / Gene expression / Genetic aspects / Humanities and Social Sciences / Humans / Immune checkpoint / Immune system / Immune Tolerance - immunology / Immunoglobulins / Immunosuppression / Immunotherapy / Infiltration / Letter / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - immunology / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Lymphocytes / Lymphocytes T / Male / Medical schools / Membrane Glycoproteins / Metastases / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Mice, SCID / Monocytes / multidisciplinary / Phenols (Class of compounds) / Protein Binding / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism / Receptors / Receptors, Cell Surface - deficiency / Receptors, Cell Surface - genetics / Receptors, Cell Surface - metabolism / Receptors, Immunologic / Receptors, Urokinase Plasminogen Activator - metabolism / Retirement benefits / Science / Science (multidisciplinary) / SHP-2 protein / Signal Transduction / Signaling / Stem cells / T cells / Therapy / Tumor Escape - drug effects / Tumor Escape - immunology / Tumors / Tyrosine / Xenograft Model Antitumor Assays