Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells
Background Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to ide...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000515.full |
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| author | Ningshao Xia Weina Chen Hisashi Arase Hai Yu Xiaoye Liu Heyu Chen Ningyan Zhang Zhiqiang An Cheng Cheng Zhang Yang Huang Jingjing Xie Xun Gui Wenxin Luo Guojin Wu Yuanzhi Chen Mi Deng Samuel John Ankit Kansagra Jaehyup Kim Cheryl Lewis Lingbo Zhang Ryan Huang |
| author_facet | Ningshao Xia Weina Chen Hisashi Arase Hai Yu Xiaoye Liu Heyu Chen Ningyan Zhang Zhiqiang An Cheng Cheng Zhang Yang Huang Jingjing Xie Xun Gui Wenxin Luo Guojin Wu Yuanzhi Chen Mi Deng Samuel John Ankit Kansagra Jaehyup Kim Cheryl Lewis Lingbo Zhang Ryan Huang |
| author_sort | Ningshao Xia |
| collection | DOAJ |
| description | Background Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.Methods First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.Results We demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.Conclusions Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy. |
| format | Article |
| id | doaj-art-87af6efac8b04399b6bee5ea7caf4ac4 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-87af6efac8b04399b6bee5ea7caf4ac42024-11-10T04:25:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2019-000515Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cellsNingshao Xia0Weina Chen1Hisashi Arase2Hai Yu3Xiaoye Liu4Heyu Chen5Ningyan Zhang6Zhiqiang An7Cheng Cheng Zhang8Yang Huang9Jingjing Xie10Xun Gui11Wenxin Luo12Guojin Wu13Yuanzhi Chen14Mi Deng15Samuel John16Ankit Kansagra17Jaehyup Kim18Cheryl Lewis19Lingbo Zhang20Ryan Huang21School of Life Sciences, Xiamen University, Xiamen, Fujian, China2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA3 Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan3 School of Public Health, Xiamen University, Xiamen, Fujian, China3University of Texas Southwestern, Dallas, TX, USA3University of Texas Southwestern, Dallas, TX, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA2 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA3University of Texas Southwestern, Dallas, TX, USA1 The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China2UT Southwestern Medical Center, Dallas, TX, USA3UT Health Science Center, Houston, TX, USAState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, ChinaNanjing Leads Biolabs Co., Ltd., Nanjing, China2 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA1 Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, USA4 Department of Pediatrics, Pediatric Hematology- Oncology, UT Southwestern Medical Center, Dallas, Texas, USA5 Department of Hematology and Oncology, UT Southwestern Medical Center, Dallas, Texas, USA7 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA6 Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA1 Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, USA1 Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, USABackground Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.Methods First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.Results We demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.Conclusions Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.https://jitc.bmj.com/content/8/2/e000515.full |
| spellingShingle | Ningshao Xia Weina Chen Hisashi Arase Hai Yu Xiaoye Liu Heyu Chen Ningyan Zhang Zhiqiang An Cheng Cheng Zhang Yang Huang Jingjing Xie Xun Gui Wenxin Luo Guojin Wu Yuanzhi Chen Mi Deng Samuel John Ankit Kansagra Jaehyup Kim Cheryl Lewis Lingbo Zhang Ryan Huang Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells Journal for ImmunoTherapy of Cancer |
| title | Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells |
| title_full | Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells |
| title_fullStr | Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells |
| title_full_unstemmed | Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells |
| title_short | Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells |
| title_sort | antagonistic anti lilrb1 monoclonal antibody regulates antitumor functions of natural killer cells |
| url | https://jitc.bmj.com/content/8/2/e000515.full |
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