Deciphering the Immunomodulatory Role of Cyclin-Dependent Kinase 4/6 Inhibitors in the Tumor Microenvironment

Abstract

Cancer is characterized by persistent cell proliferation driven by aberrant cell cycle regulation and stimulation of cyclin-dependent kinases (CDKs). A very intriguing and potential approach for the development of antitumor medicines is the suppression of CDKs that lead to induction of apoptosis and cell cycle arrest. The shift of the cell cycle from the G0/G1 phase to the S phase, which is characterized by active transcription and synthesis, depends on the development of the cyclin D-CDK4/6 complex. A precise balance between anticancer activity and general toxicity is demonstrated by CDK inhibitors, which can specifically block CDK4/6 and control the cell cycle by reducing the G1 to S phase transition. CDK4/6 inhibitors have recently been reported to exhibit significant cell growth inhibition via modulating the tumour microenvironment in cancerous cells. One significant new understanding is that these inhibitors serve important functions in the interaction among tumour cells and the host immune system in addition to being cytostatic. Herein, we discuss the biological significance of CDK4/6 inhibitors in cancer therapeutics, as well as their biological impact on T cells and other important immune cells. Furthermore, we explore the integration of preclinical findings of these pharmaceuticals' ability to enhance antitumor immunity.

Keywords: CDK4; CDK6; cancer therapy; cell cycle; immunotherapy; tumor microenvironment.

Figure 1

Regulatory role of CDK4/6 in cell cycle progression via E2F-Rb pathway.

Figure 2

Various aspects of immunomodulation via CDK4/6 inhibitors on the tumor microenvironment: induced activity of antigen presentation and PD-L1 expression on tumor cells, suppressed activity of Treg cells, enhanced cytokine secretion from CD8+ T cells and stimulated function of antigen presentation by dendritic cells.