Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions - PubMed (original) (raw)

Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

Trinidad Garcia-Iglesias et al. BMC Cancer. 2009.

Abstract

Background: Persistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. NK cells play a crucial role against tumors and virus-infected cells through a fine balance between activating and inhibitory receptors. Expression of triggering receptors NKp30, NKp44, NKp46 and NKG2D on NK cells correlates with cytolytic activity against tumor cells, but these receptors have not been studied in cervical cancer and precursor lesions. The aim of the present work was to study NKp30, NKp46, NKG2D, NKp80 and 2B4 expression in NK cells from patients with cervical cancer and precursor lesions, in the context of HPV infection.

Methods: NKp30, NKp46, NKG2D, NKp80 and 2B4 expression was analyzed by flow cytometry on NK cells from 59 patients with cervical cancer and squamous intraepithelial lesions. NK cell cytotoxicity was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay. HPV types were identified by PCR assays.

Results: We report here for the first time that NK cell-activating receptors NKp30 and NKp46 are significantly down-regulated in cervical cancer and high grade squamous intraepithelial lesion (HGSIL) patients. NCRs down-regulation correlated with low cytolytic activity, HPV-16 infection and clinical stage. NKG2D was also down-regulated in cervical cancer patients.

Conclusion: Our results suggest that NKp30, NKp46 and NKG2D down-regulation represent an evasion mechanism associated to low NK cell activity, HPV-16 infection and cervical cancer progression.

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Figures

Figure 1

Figure 1

NCRs and NKG2D expression are decreased in NK cells from cervical cancer patients. NKp30, NKp46 and NKG2D expression was analyzed by flow cytometry on NK cells from patients with cervical cancer (20 cases), HGSIL (20 cases), LGSIL (19 cases) and 20 healthy women. MFI was expressed as mean ± SD. A) NKp30; B) NKp46: * HGSIL versus LGSIL and healthy women p < 0.02, ** Invasive Ca versus LGSIL and healthy women p < 0.0001; C) NKG2D: * Invasive Ca versus LGSIL and healthy women p < 0.02; D) Two representative histograms of each group are shown, filled curve: isotype control antibody.

Figure 2

Figure 2

2B4 and NKp80 co-receptor expression is not down-regulated on NK cells from cervical cancer patients. 2B4 and NKp80 expression was analyzed by flow cytometry on NK cells from patients with cervical cancer (20 cases), HGSIL (20 cases), LGSIL (19 cases) and 20 healthy women. MFI was expressed as the mean ± SD. A) 2B4; B) NKp80; and C) Two representative histograms of each group are shown, filled curve: isotype control antibody.

Figure 3

Figure 3

NK cell specific lysis is decreased according to the natural history of cervical cancer: healthy women (6 controls) > LGSIL (6 cases) > HGSIL (5 cases) > cervical cancer (5 cases). NK cell cytotoxicity against K562 cells was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay against K562 tumor line. Significant difference at 10:1 and 30:1 E:T ratios: Invasive Ca and HGSIL versus healthy women p < 0.0001 and p < 0.002, respectively.

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