Cervical cancer cell lines expressing NKG2D-ligands are able to down-modulate the NKG2D receptor on NKL cells with functional implications

We demonstrate that NKG2D expressed on NKL cells is down-modulated by direct cell contact with cervical cancer cell lines HeLa, SiHa, and C33A, but not with non-tumorigenic keratinocytes (HaCaT). Moreover, this down-modulation had functional implications. We found expression of NKG2D-ligands in all cervical cancer cell lines, but the patterns of ligand distribution were different in each cell line. Cervical cancer cell lines co-cultured with NKL cells or fresh NK cells induced a marked diminution of NKG2D expression on NKL cells. Additionally, the cytotoxic activity of NKL cells against K562 targets was compromised after co-culture with HeLa and SiHa cells, while co-culture with C33A increased the cytotoxic activity of the NKL cells.Our results suggest that differential expression of NKG2D-ligands in cervical cancer cell lines might be associated with the down-modulation of NKG2D, as well as with changes in the cytotoxic activity of NKL cells after cell-cell contact with the tumor cells.Cervical cancer represents the third most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide [1]. Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer development [2,3]; persistence of high-risk HPV infection leads to premalignant lesions and may ultimately lead to cervical cancer in a multistep process [4,5]. The first line of defense against HPV in early infection is the innate immune system, which plays a crucial role in viral clearance [6].Natural killer (NK) cells are an important arm of the innate immune system directly involved in the spontaneous recognition and lysis of virus-infected and tumor cells. NK cells are endowed with potent cytotoxic activity, and they can also produce several cytokines, such as IFN-γ, TNF-α, GM-CSF, IL-5, and IL-8 [7-10]. Evidence is also accumulating for the crucial role of NK cells in tumor immunosurveillance [11].NK cell activity is finely regulated by an exqui