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

Abstract

BackgroundCurrent 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.MethodsFirst, 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.ResultsWe 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.ConclusionsOur 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.

The microRNA-152/human leukocyte antigen-G axis affects proliferation and immune escape of non-small cell lung cancer cells

“…Normal A549 cells or A549 cells transfected with si-HLA-G were subcutaneously inoculated in the back of mice (1 × 10 6 cells in 0.1 mL PBS). After 2 weeks, mice were administered NK-92 cells (1 × 10 7 cells in 0.1 mL PBS) in the tail vein, and ILT2 antibody (10 mg/kg) 18 or control PBS were administered intraperitoneally once a week. Tumor volumes were calculated once a week using the formula: volume = length × width 2 × 0.5.…”

The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?

“…This can effectively block the function of HLA-G as ILT2 and ILT4 bind with high affinity to HLA-G, and HLA-G appears to be the only ligand for KIR2DL4 [ 52 , 61 ]. The blockade can also restore the immunological function of immune cells as a recent study has shown that blocking ILT2 with an antibody resulted in increased tumoricidal activity of NK cells against various types of cancers [ 113 ]. However, ILT2 and ILT4 are known to bind to other classical and nonclassical HLA molecules as well, including HLA-A, -B, -C, -E and -F [ 114 ].…”

Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer

“…A polymorphic enhancer that interacts with transcription factor Yin Yang 1 (YY1) [ 77 ], and several SNPs located in the regulatory region and coding region may play roles in the expression of LILRB1 on NK cells [ 76 ]. (2) Among NK cells, LILRB1 is mainly expressed on CD56 dim NK cells [ 71 , 78 ], especially on terminally differentiated NK cells that express CD57 or multiple KIRs [ 79 , 80 ]. Adaptive NK cells, produced in response to viral infection, such as CMV or HIV infection, also highly express both CD57 and LILRB1 [ 81–83 ].…”

“…LILRB1 blockade on immune cells can improve their functions against both solid tumors [ 73 , 84 , 141 ] and hematologic malignancies [ 71 , 74 , 142 ]. In particular, LILRB1 blockade enhances the immune responses of NK cells against solid tumor cells (breast cancers and melanomas) and cells of blood cancers such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) in vitro [ 71 , 73 , 74 , 142 ]. Furthermore, LILRB1 blockade can synergistically promote the functions of immune cells in combination with other treatments in vitro .…”

“…Furthermore, LILRB1 blockade can synergistically promote the functions of immune cells in combination with other treatments in vitro . For example, LILRB1 blockade enhances tumoricidal activity of NK cells in combination with blockade of NKG2A and KIR [ 142 ], activation of NKG2D and CD16 [ 71 , 73 ], or lenalidomide, an immunomodulatory drug used for treating MM, MDS, and certain types of lymphoma. LILRB1 blockade can also improve cytolytic activity of effector CD8 T cells induced by bispecific T-cell engagers [ 84 ].…”