Emerging roles of p53 and other tumour-suppressor genes in immune regulation

Key Points

  • The role of tumour suppressors in immunity is strongly linked to maintenance of genomic integrity.

  • Impaired expression of tumour suppressor genes such as those that encode p53, retinoblastoma-associated gene 1 (RB1), phosphatase and tensin homologue (PTEN) and ARF results in susceptibility to chronic inflammatory responses triggered by pathogens and environmental stress.

  • The tumour suppressor p53 and its transcriptional targets are involved in crucial aspects of tumour and pathogen immunology and in homeostatic regulation of immune responses. This pathway has an important role in host immunity influencing both innate and adaptive immune responses.

  • A link between the tumour suppressor p53 and immune checkpoint regulators, including programmed cell death 1 (PD1), PD1 ligand 1 (PDL1) and DD1α, has been identified in cancer cells.

  • Several tumour suppressor genes including those encoding p53, ARF, RB1 and PTEN influence T cell fate by modulating the immune synapse through pattern recognition receptors, cytokine production and expression of MHC and co-inhibitory molecules.

  • Tumour suppressor gene function is emerging as a potential 'guardian of immune integrity'.

Abstract

Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour- suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity.

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Figure 1: Roles of tumour suppressor p53 in antiviral immunity.
Figure 2: Roles of tumour-suppressor genes at the immune synapse.
Figure 3: p53 as a guardian of immune integrity.

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Acknowledgements

The authors thank the members of the Lee laboratory for their helpful discussions. This work is supported by the grants 1RO1CA195534, 1R01CA203552, PO1CA80058, MGH ECOR funding, and the Breast Cancer Research Foundation.

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Correspondence to Stuart A. Aaronson or Sam W. Lee.

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Glossary

ARF–p53 tumour suppressor pathway

ARF regulates p53 activity through the direct binding to MDM2 to neutralize its function, which initiates transcription factor activity of p53. The ARF–p53 axis is essential for the detection and removal of damaged cells, and the inactivation of ARF and p53 occurs in a mutually exclusive manner in human cancers.

Immune checkpoint pathways

Immune checkpoints are used by the host to regulate immune responses and prevent immune hyperactivation from harming normal tissues.

'Eat-me' signal

Apoptotic cells expose markers known as eat-me signals on their surface that are recognized by phagocytes through specific engulfment receptors.

Congenital retinoblastoma

Congenital retinoblastoma is the most common eye tumour in children and the third most common cancer overall affecting children; it is caused by a germline mutation in RB1.

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Muñoz-Fontela, C., Mandinova, A., Aaronson, S. et al. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 16, 741–750 (2016). https://doi.org/10.1038/nri.2016.99

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