The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion.
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 natural killer (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 similar to that of 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 nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G(+) cancer cells, MCF-7 and JEG-3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G(+) breast cancer cells and KIR2DL4(+) tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 cases; 91.7%; χ(2) = 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 subsequent metastasis.
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Chiyuki
C
Ueshima
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. trkataoka@yahoo.co.jp.
Tatsuki R
TR
Kataoka
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Masahiro
M
Hirata
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Ayako
A
Furuhata
Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan.
Eiji
E
Suzuki
Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan.
Masakazu
M
Toi
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Tatsuaki
T
Tsuruyama
Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan.
Yoshimichi
Y
Okayama
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Hironori
H
Haga
D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D059951:HLA-G Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D054345:Receptors, KIR2DL4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D059951:HLA-G Antigens; D054345:Receptors, KIR2DL4; D007073:Immunoglobulin E; D019009:Proto-Oncogene Proteins c-kit; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11