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. 2009 May;58(5):641-52.
doi: 10.1007/s00262-008-0585-3. Epub 2008 Sep 13.

Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis

Kui Li  1 , Masaki Mandai, Junzo Hamanishi, Noriomi Matsumura, Ayako Suzuki, Haruhiko Yagi, Ken Yamaguchi, Tsukasa Baba, Shingo Fujii, Ikuo Konishi
Affiliations

Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis

Kui Li et al. Cancer Immunol Immunother. 2009 May.

Abstract

Objective: To investigate the clinical significance of the expression of the NKG2D ligands MICA/B and ULBP2 in ovarian cancer.

Methods: Eighty-two ovarian cancer patients and six patients without ovarian cancer from Department of Obstetrics and Gynecology of Kyoto University Hospital were enrolled in this study between 1993 and 2003. Expression of MICA/B, ULBP2, and CD57 in ovarian cancer tissue and normal ovary tissue was evaluated by immunohistochemical staining, and the relationship of these results to relevant clinical patient data was analyzed. Expression of MICs, ULBP2, and HLA-class I molecules in 33 ovarian cancer cell lines and two normal ovarian epithelial cell lines, as well as levels of soluble MICs and ULBP2 in the culture supernatants, were measured.

Results: Expression of MICA/B and ULBP2 was detected in 97.6 and 82.9% of ovarian cancer cells, respectively, whereas neither was expressed on normal ovarian epithelium. The expression of MICA/B in ovarian cancer was highly correlated with that of ULBP2. Strong expression of ULBP2 in ovarian cancer cells was correlated with less intraepithelial infiltration of T cells and bad prognoses for patients, suggesting that ULBP2 expression is a prognostic indicator in ovarian cancer. The expression of NKG2D ligands did not correlate with the levels of the soluble forms of the ligands.

Conclusions: High expression of ULBP2 is an indicator of poor prognosis in ovarian cancer and may relate to T cell dysfunction in the tumor microenvironment.

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Figures

Fig. 1
Fig. 1
Immunohistochemical staining of human ovarian cancer tissues using anti-MIC, ULBP2, and CD57 antibodies. a Representative staining patterns of MICs. b Representative staining patterns of ULBP2. c Representative staining patterns of CD57+ NK cells. Spleens were used as positive controls (magnification, ×200)
Fig. 2
Fig. 2
Overall and progression-free survival analyses of patients with ovarian cancer according to the expression of MICA/B and ULBP2 and tumor infiltration by CD57+ NK cells. a Kaplan–Meier curves according to high (n = 20) and low (n = 62) ULBP2 expressions. b Kaplan–Meier curves according to high (n = 42) and low (n = 40) MIC expressions. c Kaplan–Meier curves according to tumor infiltration by CD57+ NK cells. Group 1 (n = 27), patients without tumor infiltration by NK cells; Group 2 (n = 22), patients only with intra-epithelial infiltration by NK cells; Group 3 (n = 5), patients with intra-stromal infiltration NK cells only; Group 4 (n = 28), patients with both intra-stromal and intra-epithelial infiltration by NK cells. The difference of overall survival between Group 2 (106 ± 11 months) and 3 (58 ± 19 months) is statistically significant, P < 0.05
Fig. 3
Fig. 3
Representative flow cytometry results for ovarian cell lines. The figure shows the expression of MICs (solid line) and ULBP2 (dot line), the filled histograms represent the isotype control. a Normal ovarian cell line OSE6. b Endometrioid adenocarcinoma cell line OV2008. c Serous adenocarcinoma cell line OVCAR-3. d Clear cell carcinoma cell line TOV-21G. e Undifferentiated carcinoma cell line A2780
Fig. 4
Fig. 4
The relationship between the ligands expression on the cell membrane and the soluble molecules levels in supernatant of ovarian cancer cell lines. X-axis represents soluble NKG2D ligands in supernatant which was detected by ELISA. Y-axis represents expression of NKG2D ligands detected by flow cytometry, which is shown as comparative fluorescence density compared to isotype control (log). a There was no correlation between the soluble MICA and the cell surface expression of MICs. b There was no correlation between the soluble MICB and the cell surface expression of MICs. c There was no correlation between the soluble MICs (sum of the soluble MICA and MICB) and the cell surface expression of MICs. d There was no correlation between the soluble ULBP2 and the cell surface expression of ULBP2
Fig. 5
Fig. 5
The relationship between the immunohistochemical expression of MICA/B in the cancer tissue (x-axis) and the soluble molecules levels in sera of ovarian cancer patients (y-axis). a There was no correlation between the soluble MICA and the cancer expression of MICs. b There was no correlation between the soluble MICB and the cancer expression of MICs. c There was no correlation between the soluble MICs (sum of the soluble MICA and MICB) and the cancer expression of MICs. Intensity of MICs: 0 negative expression, 1 weak expression and 2 strong expression in immunohistochemistry
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