NK Cell–Specific CDK8 Deletion Enhances Antitumor Responses

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 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..

Lack of FcRn Impairs Natural Killer Cell Development and Functions in the Tumor Microenvironment

“…These cytokines are involved in proliferation, differentiation/maturation of NK cells and enhance their effector functions ( 36 , 37 ). Pre-activation of NK cells with IL-2 or IL-12, IL-15 and IL-18 results in the generation of NK cells efficient to target and kill tumor cells ( 24 , 38 ). The lower expression of CD107a and IFN-γ synthesis (after IL-2 or IL-12, IL-15, and IL-18 activation) as well as the increased cell death (in the presence of IL-2) in FcRn −/− NK cells, support an impaired response of NK cells to cytokines in an FcRn −/− deprived microenvironment.…”

“…For in vitro cytotoxicity assays, isolated NK cells were maintained overnight in RPMI 1640 complete medium supplemented with 50 U/ml rhIL2 and mixed at indicated effector: target ratios (10:1, 5:1 and 1:1) with carboxyfluorescein diacetate succinimidyl ester (CFSE, TonboBio) labeled target YAC-1 cells as previously described ( 23 , 24 ). After 4-h of incubation at 37°C, the specific target cell lysis was assessed by flow cytometry ( 23 ).…”

<p>Circ_0005576 Promotes Malignant Progression Through miR-874/CDK8 Axis in Colorectal Cancer</p>

“…CDK8 is a member of the cyclin-dependent kinase family. 22 As a key regulator of the cell cycle, CDK8 was reported to regulate the G1/S phase of the cell cycle by activating Cyclin C. 23,24 In this paper, circ_0005576 knockdown increased CRC cells in G1 phase and decreased cells in S phase. However, the overexpression of CDK8 significantly reversed this effect.…”

The CDK8 inhibitor DCA promotes a tolerogenic chemical immunophenotype in CD4+ T cells via a novel CDK8-GATA3-FOXP3 pathway

“…We and others have previously shown that DCA inhibits CDK8 kinase activity with immunomodulatory effects (11,(20)(21)(22)(23). We used two different approaches to validate CDK8 as the Treg-relevant mechanistic target of DCA.…”

“…We previously showed that c-Jun phosphorylation by CDK8 regulates IL-10 production in innate immune cells (11). Deletion of CDK8 in NK cells enhances cytotoxicity and improves tumor surveillance (20,21). Furthermore, CDK8/19 inhibitors promote Treg differentiation (22,23).…”