TY - JOUR
T1 - Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells
AU - Chen, Heyu
AU - Chen, Yuanzhi
AU - Deng, Mi
AU - John, Samuel
AU - Gui, Xun
AU - Kansagra, Ankit
AU - Chen, Weina
AU - Kim, Jaehyup
AU - Lewis, Cheryl
AU - Wu, Guojin
AU - Xie, Jingjing
AU - Zhang, Lingbo
AU - Huang, Ryan
AU - Liu, Xiaoye
AU - Arase, Hisashi
AU - Huang, Yang
AU - Yu, Hai
AU - Luo, Wenxin
AU - Xia, Ningshao
AU - Zhang, Ningyan
AU - An, Zhiqiang
AU - Zhang, Cheng Cheng
N1 - Publisher Copyright:
©
PY - 2020/8/7
Y1 - 2020/8/7
N2 - 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.
AB - 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.
KW - antibodies, neoplasm
KW - cytotoxicity, immunologic
KW - immunotherapy
KW - killer cells, natural
KW - receptors, immunologic
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U2 - 10.1136/jitc-2019-000515
DO - 10.1136/jitc-2019-000515
M3 - Article
C2 - 32771992
AN - SCOPUS:85089262058
SN - 2051-1426
VL - 8
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 2
M1 - e000515
ER -