Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Heyu Chen, Yuanzhi Chen, Mi Deng, Samuel John, Xun Gui, Ankit Kansagra, Weina Chen, Jaehyup Kim, Cheryl Lewis, Guojin Wu, Jingjing Xie, Lingbo Zhang, Ryan Huang, Xiaoye Liu, Hisashi Arase, Yang Huang, Hai Yu, Wenxin Luo, Ningshao Xia, Ningyan ZhangZhiqiang An, Cheng Cheng Zhang

Research output: Contribution to journalArticle

Abstract

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-2R 3-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.

Original languageEnglish (US)
Article numbere000515
JournalJournal for ImmunoTherapy of Cancer
Volume8
Issue number2
DOIs
StatePublished - Aug 7 2020

Keywords

  • antibodies, neoplasm
  • cytotoxicity, immunologic
  • immunotherapy
  • killer cells, natural
  • receptors, immunologic

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Chen, H., Chen, Y., Deng, M., John, S., Gui, X., Kansagra, A., Chen, W., Kim, J., Lewis, C., Wu, G., Xie, J., Zhang, L., Huang, R., Liu, X., Arase, H., Huang, Y., Yu, H., Luo, W., Xia, N., ... Zhang, C. C. (2020). Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells. Journal for ImmunoTherapy of Cancer, 8(2), [e000515]. https://doi.org/10.1136/jitc-2019-000515