Abstract
BackgroundPersistent 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.MethodsNKp30, 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.ResultsWe 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.ConclusionOur 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.
Highlights
Persistent high risk Human papillomavirus (HPV) infection can lead to cervical cancer, the second most common malignant tumor in women worldwide
There was no significant difference in mean age ± SD between cervical cancer patients (51.55 ± 14.55), high grade squamous intraepithelial lesion (HGSIL) patients (41.29 ± 10.89), low grade squamous intraepithelial lesions (LGSIL) patients (38.52 ± 9.72) and controls (44.10 ± 9.56)
Arguments that may point to an important role of NK cells in the natural history of cervical cancer are: a) NK cells can recognize and either destroy virally infected cells or control the infection via cytokines (IFN-gamma and TNF-alpha), b) HPV-associated cervical tumors frequently exhibit a reduction in MHC class I expression as an immune evasion strategy, c) NK cell receptor ligands (MICA and CD155) are differentially expressed during progression to cervical cancer [15,18,19]
Summary
Persistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. 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. Cervical carcinogenesis implies HPV infection, viral persistence, progression and invasion [2]. Both innate and adaptive immune responses play a complex role against HPV infection. Innate immune response acts directly or indirectly against viral agents, through TLRs activation, dendritic cell presentation and NK cell function at cervical tissue level [8,9,10,11]
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