NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses

Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8...

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Published in:Cancer immunology research 2018-04, Vol.6 (4), p.458-466
Main Authors: Witalisz-Siepracka, Agnieszka, Gotthardt, Dagmar, Prchal-Murphy, Michaela, Didara, Zrinka, Menzl, Ingeborg, Prinz, Daniela, Edlinger, Leo, Putz, Eva Maria, Sexl, Veronika
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - genetics
Cell Line, Tumor
Cyclin-Dependent Kinase 8 - genetics
Cytotoxicity, Immunologic
Disease Models, Animal
Gene Deletion
Immunity, Innate
Killer Cells, Natural - cytology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Melanoma, Experimental
Mice
Mice, Transgenic
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - pathology
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Summary:Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses. In this study, we investigated the role of CDK8 in NK-cell function using mice with conditional ablation of CDK8 in NKp46 cells ( ). Regardless of CDK8 expression, NK cells develop and mature normally in bone marrow and spleen. However, CDK8 deletion increased expression of the lytic molecule perforin, which correlated with enhanced NK-cell cytotoxicity This translates into improved NK cell-mediated tumor surveillance in three independent models: B16F10 melanoma, lymphoma, and a slowly developing oncogene-driven leukemia. Our results thereby define a suppressive effect of CDK8 on NK-cell activity. Therapies that target CDK8 in cancer patients may enhance NK-cell responses against tumor cells. .
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.cir-17-0183