NK Cell–Specific CDK8 Deletion Enhances Antitumor Responses
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Abstract
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 in vivo using mice with conditional ablation of CDK8 in NKp46 + cells ( Cdk8 fl/fl Ncr1Cre ). 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 in vitro This translates into improved NK cell-mediated tumor surveillance in vivo in three independent models: B16F10 melanoma, v-abl + 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. Cancer Immunol Res; 6(4); 458-66. ©2018 AACR .
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Specific deletion of CDK8 in NK cells results in enhancement of their anti-tumor responses.
“Specific deletion of CDK8 in NK cells results in an enhancement of their anti-tumor responses (Witalisz-Siepracka et al., 2018)”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Witalisz-Siepracka et al., 2018
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Debnath, T., Jin, W. J., Patel, R. B., Carlson, P. M., Rahman, M. M., Berg, T. J., Kerr, C. P., Welch, R., Wang, Y., Hyun, M., et al. (2026) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-25-1475
The Role of Transcriptional and Atypical Cyclin-Dependent Protein Kinases in Melanoma
Kaszubski, J., Gagat, M., Wawrzyniak, A., & Żuryń, A. (2026) · Cancers · doi:10.3390/cancers18172726
A guide to transcriptional cyclin‐dependent kinases in cancer
Devlin, J. R., Kyheröinen, S., & Johnstone, R. W. (2026) · FEBS Journal · doi:10.1111/febs.70731
BindingDB Entry 50018624: Angel or Devil ? - CDK8 as the new drug target.
BindingDB (2024) · UC San Diego · doi:10.7270/q20006bk
- Authors
- Witalisz-Siepracka, A., Gotthardt, D., Prchal-Murphy, M., Didara, Z., Menzl, I., Prinz, D., Edlinger, L., Putz, E. M., & Sexl, V.
- Affiliations
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
- University of Veterinary Medicine Vienna (AT)
- Venue
- Cancer Immunology Research
- Published
- 2018-04-01
- Volume
- 6
- Issue
- 4
- Pages
- 458-466
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- OpenAlex
- W2785341808
- Cited by
- 47
- References
- 43
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 12 · 2019: 6 · 2018: 3
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund FWF (P28571)
- Schroedinger Fellowship (J-3635)
- PhD program "Inflammation and Immunity" (FWF W1212)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- CDK8, natural killer cells, NK cell cytotoxicity, perforin, conditional gene deletion, NKp46, melanoma, leukemia, antitumor immunity
- MeSH terms
- Animals, Cell Differentiation, Cytotoxicity, Immunologic, Disease Models, Animal, Immunity, Innate, Killer Cells, Natural, Melanoma, Experimental, Mice, Transgenic, Neoplasms, Gene Deletion, Cell Line, Tumor, Mice, Cyclin-Dependent Kinase 8
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