CDK2 Inhibition Enhances Antitumor Immunity by Increasing IFN Response to Endogenous Retroviruses

Abstract

Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8+ T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.

MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

“…Of most interest to us because of potential novelty for treating phenotypic plastic PCa was the cell cycle related cyclin-dependents kinases (CDK) which included CDK2, CDK5, and CDK7. Based on information gained from this analysis and the success of CDK inhibitors in other cancers (49,50), we applied the DEMETER computational method (44) to infer the dependency of these three CDK genes in the human PCa cell lines mentioned in figure 3. We found that CDK2 demonstrated consistent dependency within all PCa cell lines including the H660 cell line ( Figure 5C ).…”

“…Tissue sections were imaged using an BZ-X810 microscope (Keyence). Images were de-identified and 5 random fields per section were run through QuPath image analysis software (49) to quantify positive DAB-stained cells (as a percentage of total cells).…”

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

“…across 33 different tumors confirmed the involvement of CDK2 in activating immune response, cell adhesion, migration, and the PI3K‐AKT signaling pathway. The study by Chen et al 21 . found that inhibiting CDK2 promotes antitumor immunity in fibrosarcoma and lung cancer mouse models.…”

“…Fadraciclib, a highly selective inhibitor targeting CDK2, has shown antitumor effects in TNBC based on studies by Frame et al 19 The research by Liu et al 20 across 33 different tumors confirmed the involvement of CDK2 in activating immune response, cell adhesion, migration, and the PI3K-AKT signaling pathway. The study by Chen et al 21 found that inhibiting CDK2 promotes antitumor immunity in fibrosarcoma and lung cancer mouse models.…”

Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response

“…The transcription of multiple proinflammatory genes is upregulated in a CDK-dependent fashion throughout the G1 phase 5 . In the context of antitumor immunity in fibrosarcoma and lung carcinoma, inhibiting CDK2 leads to the RB protein being phosphorylated, which results in increased production of type I IFN 6 . Another study demonstrated that inhibiting CDKs or the knockdown of CDKs activities caused a significant blockade in IFN release from culture supernatants 7 .…”