Activating NK cell receptor ligands are differentially expressed during progression to cervical cancer
Sonja Textor1, Matthias Dürst, Lars Jansen
1Division of Innate Immunity, German Cancer Research Center, Heidelberg, Germany.
Abstract:
Human papillomavirus-induced cervical carcinomas often show impaired expression of MHC class I molecules resulting in the inability of tumor cells to directly present viral peptides to cytotoxic T lymphocytes. Loss of MHC class I expression combined with the expression of activating NK cell receptor ligands renders tumor cells potentially susceptible to NK cell attack. Thus, in this study, we analyzed the expression of activating NK cell receptor ligands, NK cell accumulation and activation status in situ in normal ectocervical tissue (NCT), cervical intraepithelial neoplasia (CIN) and squamous cervical carcinoma (CxCa). We observed that expression of the DNAM-1 ligand CD155 was frequently upregulated in CxCa, but not in CIN. The NKG2D ligand MICA was upregulated in fewer CxCa biopsies. In contrast, another NKG2D ligand ULBP2 was preferentially expressed in differentiated epithelial cells of NCT. Increased numbers of NK cells were detected in CIN as compared to NCT and CxCa. Expression of activating NK cell receptor ligands combined with loss of MHC class I was not correlated with enhanced NK cell accumulation or activation status. Furthermore, we demonstrate that cervical cancer cell lines are killed by the NK cell line, NKL, in a NKG2D- and DNAM-1-dependent manner in vitro. Since a significant number of CxCa biopsies showed low MHC class I expression combined with high expression of one or more of the tested activating NK cell receptor ligands, we conclude that CxCa might be a promising target for NK cell-based adoptive immunotherapy.
Insights
Human papillomavirus-induced cervical cancers (CxCa) often evade immune detection. This study found that CxCa may be treatable with NK cell-based immunotherapy due to specific immune ligand expression.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Human papillomavirus-induced cervical carcinomas exhibit reduced MHC class I, hindering T cell recognition.
- Loss of MHC class I and expression of activating NK cell receptor ligands can make tumor cells vulnerable to NK cell attack.
Purpose of the Study:
- To investigate the expression of activating NK cell receptor ligands, NK cell infiltration, and activation status in normal cervical tissue, cervical intraepithelial neoplasia, and cervical squamous cell carcinoma.
- To evaluate the potential of cervical cancer as a target for NK cell-based immunotherapy.
Main Methods:
- Analysis of activating NK cell receptor ligand expression (CD155, MICA, ULBP2) in normal ectocervical tissue (NCT), cervical intraepithelial neoplasia (CIN), and squamous cervical carcinoma (CxCa) biopsies.
- Assessment of NK cell accumulation and activation status in situ.
- In vitro killing assays using cervical cancer cell lines and the NKL cell line, examining NKG2D and DNAM-1 dependence.
Main Results:
- CD155 was frequently upregulated in CxCa, while MICA was upregulated in fewer CxCa biopsies. ULBP2 was mainly expressed in NCT.
- Increased NK cell numbers were observed in CIN compared to NCT and CxCa.
- Loss of MHC class I combined with activating ligand expression did not correlate with increased NK cell accumulation or activation.
- Cervical cancer cell lines were killed by NKL cells in a NKG2D- and DNAM-1-dependent manner in vitro.
Conclusions:
- Cervical squamous cell carcinoma exhibits altered expression of activating NK cell receptor ligands, with CD155 upregulation in CxCa.
- Despite increased NK cell numbers in CIN, the combination of low MHC class I and high activating ligand expression in CxCa suggests potential for NK cell-mediated tumor cell killing.
- Cervical cancer is a promising candidate for NK cell-based adoptive immunotherapy.
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