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

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.

Figure 1. Roles of tumour suppressor p53 in antiviral immunity

p53 is activated in response to type I IFN signalling due to the presence of IFN-stimulated response elements (ISRE) within the p53 promoter sequence. Activation of p53 leads to the upregulation of genes that can promote cell cycle arrest, apoptosis and intracellular immunity. Several p53 target genes are in turn involved in driving IFN production and signalling, including TLR3, IRF5, ISG15 and IRF9. This provides a positive feedback loop on the type I IFN pathway with important implications in immune responses, in particular against viral infections.

Figure 2. Roles of tumour-suppressor genes at the immune synapsis

The synapsis between antigen-presenting cells such as DCs and T cells regulates T cell fate through multiple mechanisms. The tumour suppressor p53 influences many aspects of the immune synapsis including activation through pattern recognition receptors, cytokine production, and expression of MHC and co-inhibitory molecules. In T cells, p53 regulates expression of Foxp3. Other tumor suppressors also modulate the immune synapsis by influencing DC maturation and cytokine production among others.

Figure 3. p53 as a guardian of immune integrity

Owing to its roles in inducing cell cycle arrest and apoptosis in stressed cells, p53 has been referred to as the ‘guardian of the genome’. More recently, it has become apparent that p53 has important roles in promoting immune tolerance. p53 induces the expression of immune checkpoint molecules such as PD-1, PD-L1 and DD1α (also known as VISTA and PD-H1), which negatively regulate effector T cell responses. Furthermore, p53 enhances the detection and uptake of apoptotic cells by the immune system. As such, we suggest that p53 can also be considered as a guardian of immune integrity.