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  • Review Article
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Immunomodulation by anticancer cell cycle inhibitors

Nature Reviews Immunology volume 20, pages 669–679 (2020)Cite this article

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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.

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Fig. 1: Cyclins and cyclin-dependent kinases in immune cells.
Fig. 2: Immunostimulation upon cyclin-dependent kinase inhibition.
Fig. 3: Immunoevasion upon cyclin-dependent kinase inhibition.

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Acknowledgements

G.P., S.C.F. and L.G. are supported by the 2019 Laura Ziskin Prize in Translational Research (no. ZP-6177) from the Stand Up to Cancer initiative. S.C.-K. and L.G. are supported by a Mantle Cell Lymphoma Research Initiative grant from the Leukemia and Lymphoma Society. S.C.-K. is further supported by a P01 grant (no. CA214274) from the National Institutes of Health/National Cancer Institute. L.G. is further supported by a Breakthrough Level 2 grant from the US Department of Defense, Breast Cancer Research Program (no. BC180476P1), a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), a Rapid Response Grant from the Functional Genomics Initiative (New York, USA), industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, USA), and donations from Phosplatin (New York, USA), the Luke Heller TECPR2 Foundation (Boston, USA) and Sotio a.s. (Prague, Czech Republic).

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Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Giulia Petroni, Silvia C. Formenti & Lorenzo Galluzzi

  2. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Silvia C. Formenti, Selina Chen-Kiang & Lorenzo Galluzzi

  3. Department of Pathology, Weill Cornell Medical College, New York, NY, USA

    Selina Chen-Kiang

  4. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

  5. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

    Lorenzo Galluzzi

  6. Université de Paris, Paris, France

    Lorenzo Galluzzi

Authors
  1. Giulia Petroni
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  3. Selina Chen-Kiang
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  4. Lorenzo Galluzzi
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Contributions

G.P. and L.G. conceived the idea for the Review and wrote the first version of the manuscript, with constructive input from S.C.F. and S.C.-K. G.P. prepared display items under the supervision of L.G. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Lorenzo Galluzzi.

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Competing interests

L.G. received consulting fees from OmniSEQ, Astra Zeneca, Inzen and the Luke Heller TECPR2 Foundation, and is a member of the Scientific Advisory Committee of Boehringer Ingelheim, The Longevity Labs and OmniSEQ. G.P., S.C.F. and S.C.-K. declare no competing interests.

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Nature Reviews Immunology thanks A. Wells and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Retinoblastoma 1

(RB1). A multifunctional tumour suppressor protein that is dysfunctional in most human cancers. Biallelic germline loss of RB1 is associated with hereditary paediatric retinoblastoma.

Hormone receptor-positive breast cancer

A common form of breast cancer characterized by the expression of oestrogen receptor 1 and/or progesterone receptor.

13q14 deletion

A frequent genomic alteration, consisting of the deletion of a portion of the long arm of chromosome 13 that includes the retinoblastoma 1 (RB1) gene.

Type 1 diabetes

An autoimmune form of glucose intolerance that originates from the immunological destruction of insulin-producing pancreatic β-cells and, hence, can be treated with insulin administration.

Notch signalling

A highly conserved signal transduction pathway that regulates the differentiation of multiple cell types.

Histone deacetylase

(HDAC). One of multiple enzymes that repress transcriptional programmes by removing functional acetyl groups from histones.

Mediator complex

A tetrameric cyclin-dependent kinase 8 (CDK8)-containing or CDK19-containing complex that is involved in transcriptional regulation.

Senescence surveillance

An immunological mechanism that ensures the natural killer cell-dependent and T cell-dependent elimination of potentially pathogenic senescent cells.

Hepatic stellate cells

Liver-resident stromal cells that are largely found in proximity of the vasculature and contribute to hepatic fibrosis and carcinogenesis.

The Cancer Genome Atlas

A large, publicly available patient data set containing mutational, transcriptional and pathophysiological data from multiple independent cohorts of patients with cancer.

Mitogen-activated protein kinase

(MAPK). The generic name commonly used to indicate one or more members of a large serine/threonine protein kinase family involved in numerous cellular functions, including proliferation.

Patient-derived xenografts

Patient-derived tumour samples implanted into immunologically compatible mice for investigational purposes.

Endogenous retroviral elements

DNA sequences encoded (but normally not expressed) by the genome of multiple mammals (including humans and mice) that resemble modern retroviruses.

Micronucleation

The accumulation of small nuclear structures containing one or a few chromosomes resulting from one or more rounds of defective mitosis.

Viral mimicry

The state whereby mammalian cells that are not exposed to an exogenous viral infection activate one or more pathways involved in viral resistance, including antigen presentation and interferon signalling.

Senolytic

An agent that specifically kills senescent cells.

Autophagy

A conserved mechanism through which all eukaryotic cells can dispose of superfluous or potentially toxic cytosolic material via lysosomal degradation.

Cytokine release syndrome

A life-threatening condition characterized by systemic inflammation that can arise as a complication of some diseases, or as an adverse effect of some immunotherapeutic agents.

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Petroni, G., Formenti, S.C., Chen-Kiang, S. et al. Immunomodulation by anticancer cell cycle inhibitors. Nat Rev Immunol 20, 669–679 (2020). https://doi.org/10.1038/s41577-020-0300-y

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