CDK4/6 inhibition triggers anti-tumor immunity

By S. Goel, Molly J Decristo, April C. Watt, Haley BrinJones, Jaclyn Sceneay, Ben B. Li, N. Khan, Jessalyn M. Ubellacker, Shaozhen Xie, O. Metzger-Filho and 10 more. Nature, 2017

1,277 citations recorded by the source corpus.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/4290484c6d03c7eb3a71cf81a3fe70a41d0d4ed4

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Citations in the corpus

CCRK is a novel signalling hub exploitable in cancer immunotherapy (2018, positive): “A recent study on the mouse models of breast carcinoma and retinoblastoma demonstrated that CDK4/6 inhibitors could stimulate the production of type III interferons and hence boost tumor antigen presentation (Goel et al., 2017).”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…between ERVs and immune infiltration and activation, as well as the role for EMAs as adjuvants for ICI therapy via ERV modulation, requires further investigation, there is growing interest in the role of ERV induction as a mechanism to enhance response to PD-1 blockade (Goel et al, 2017).”
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade (2018, positive): “CDK4/6 Inhibitors Repress the Resistance Program in Melanoma Cells We therefore tested if CDK4/6i could shift the malignant cell population to a less immune resistant state.”
Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, positive): “…that another inhibitor of CDK4/6, abemaciclib, increased immunogenicity of cancer cells via an Rb-dependent mechanism, which activates tumor cell expression of endogenous retroviral elements, thereby stimulating production of type III interferons and antigen presentation by tumor cells 30 .”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “Additional investigation of the molecular programs underlying differential expression of CXCL1, CSF3, and other potential mediators of the T cell low TME—including our observation that T cell low tumors enriched cell-cycle signatures (Goel et al., 2017)—are likely to provide new therapeutic opportun”