Immunomodulation by anticancer cell cycle inhibitors

Abstract

Cell cycle proteins that are often dysregulated in malignant cells, such as cyclin-dependent kinase 4 (CDK4) and CDK6, have attracted considerable interest as potential targets for cancer therapy. In this context, multiple inhibitors of CDK4 and CDK6 have been developed, including three small molecules (palbociclib, abemaciclib and ribociclib) that are currently approved for the treatment of patients with breast cancer and are being extensively tested in individuals with other solid and haematological malignancies. Accumulating preclinical and clinical evidence indicates that the anticancer activity of CDK4/CDK6 inhibitors results not only from their ability to block the cell cycle in malignant cells but also from a range of immunostimulatory effects. In this Review, we discuss the ability of anticancer cell cycle inhibitors to modulate various immune functions in support of effective antitumour immunity.

Fig. 1 |. Cyclins and cyclin-dependent kinases in immune cells.

Genetic data from whole-body or conditional knockout studies show that numerous immune cell types require the cell-intrinsic functions of specific cyclins (CCNs) and cyclin-dependent kinases (CDKs) for their development, maturation or activation. Importantly, the ability of specific CCNs and CDKs to regulate immune functions can involve cell cycle-dependent mechanisms (red arrows) as well as cell cycle-independent mechanisms (blue arrows). MED, mediator complex subunit; NK, natural killer; T_reg cell, regulatory T cell.

Fig. 2 |. Immunostimulation upon cyclin-dependent kinase inhibition.

Inhibitors of cyclin-dependent kinase 4 (CDK4) and CDK6 — herein referred to as CDK4/CDK6 inhibitors — can have various immunomodulatory effects as they target both malignant and non-malignant components of the tumour microenvironment. CDK4/CDK6 inhibition has been associated with immunostimulatory effects that largely reflect increased antigen presentation by tumour cells (1); the reactivation of endogenous retroviruses (ERVs) and the consequent secretion of type III interferon (2); production of multiple pro-inflammatory cytokines and chemokines, such as CC-chemokine ligand 5 (CCL5), as part of the senescence-associated secretory phenotype (SASP) (3); direct activation of effector T cells upon derepression of nuclear factor of activated T cells 1 (NFATC1; best known as NFAT) (4); or inhibition of regulatory T (T_reg) cell proliferation through repression of DNA methyltransferase 1 (DNMT1) expression (which is expressed downstream of the release of retinoblastoma 1 (RB1) from E2F family transcription factors by active CDK4/CDK6), and consequent upregulation of the cell cycle inhibitor p21^CIP1 (5). CCND, D-type cyclin; dsRNA, double-stranded RNA; P, phosphate.

Fig. 3 |. Immunoevasion upon cyclin-dependent kinase inhibition.

Malignant cells harness numerous strategies to escape immunosurveillance in the context of inhibition of cyclin-dependent kinase 4 (CDK4) and CDK6. For example, specific components of the senescence-associated secretory phenotype (SASP) driven by CDK4/CDK6 inhibitors, such as CC-chemokine ligand 2 (CCL2) and transforming growth factor-β (TGFβ), favour the proliferation of senescence-resistant neighbouring tumour cells and the establishment of local immunosuppression by paracrine mechanisms. Moreover, inhibition of speckle type BTB/POZ protein (SPOP) by CDK4/CDK6 inhibitors limits PDL1 degradation by the proteasome, hence promoting immunosuppression via tumour cell-intrinsic pathways. Strategies that prevent or compensate for such mechanisms may be instrumental for the management of human tumours that are or become resistant to CDK4/CDK6 inhibitors. MDM2, MDM2 proto-oncogene; PTEN, phosphatase and tensin homologue; TIL, tumour-infiltrating lymphocyte.