The killer cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human NK cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similarly to NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human non-neoplastic mast cells including pathological specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production of PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP)-2. Next, we performed the co-culture assay between LAD2 cells and the HLA-G-positive cancer cells, MCF-7 and JEG-3. The assay revealed that the KIR2DL4 on LAD2 cells enhanced the MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G-positive breast cancer cells and KIR2DL4-positive tissue mast cells (observed in 12 of 36 cases, 33.3%) were statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 case, 91.7%) (χ2 = 7.439, P<0.01, degrees of freedom; 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G-expressing cancer invasion and the followed metastasis.
- Received October 22, 2014.
- Revision received February 9, 2015.
- Accepted February 24, 2015.
- Copyright © 2015, American Association for Cancer Research.