P53: A Guardian of Immunity Becomes Its Saboteur through Mutation

Abstract

Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for immunotherapy. At the heart of tumour suppression is p53, which was discovered in the context of viral infection and now emerges as a significant player in normal and cancer immunity. Wild-type p53 (wt p53) plays fundamental roles in cancer immunity and inflammation. Mutations in p53 not only cripple wt p53 immune functions but also sinisterly subvert the immune function through its neomorphic gain-of-functions (GOFs). The prevalence of mutant p53 across different types of human cancers, which are associated with inflammatory and immune dysfunction, further implicates mutant p53 in modulating cancer immunity, thereby promoting tumorigenesis, metastasis and invasion. In this review, we discuss several mutant p53 immune GOFs in the context of the established roles of wt p53 in regulating and responding to tumour-associated inflammation, and regulating innate and adaptive immunity. We discuss the capacity of mutant p53 to alter the tumour milieu to support immune dysfunction, modulate toll-like receptor (TLR) signalling pathways to disrupt innate immunity and subvert cell-mediated immunity in favour of immune privilege and survival. Furthermore, we expose the potential and challenges associated with mutant p53 as a cancer immunotherapy target and underscore existing therapies that may benefit from inquiry into cancer p53 status.

Keywords: cancer immunity; cancer immunotherapy; gain of function; inflammation; mutant p53.

Figure 1

Mutant p53 feeds off and fuels inflammation. Wild-type p53 (Wt p53) contributes to effective tumour immunity through its roles in senescence, apoptosis, autophagy and ROS regulation, as well as established roles in regulating immune response. Mutant p53 is able to subvert these effects through dominant negative effects and novel tumourigenic functions mediated through the inflammatory pathways of NF-κB and signal transducer and activator of transcription 3 (STAT3). The excessive production of reactive oxygen species (ROS) can fuel inflammatory microenvironments without the regulation of wt p53, consequently feeding mutant p53 function and tipping the scales toward tumorigenesis. It is worth noting that innate immunity is not included in this model and is discussed later on.

Figure 2

Mutant p53 alters its immunogenic niche. The tumour microenvironment is comprised of cellular and molecular components which shape the immune niche of the growing tumour. (A) Normal fibroblasts help mediate immunosurveillance by modulating anti-tumour immune cell infiltration and employing the IFN-β/p53 axis of regulation to activate anti-tumour responses. (B) Mutant p53 in the tumour alters the crosstalk between the tumour and its microenvironment, suppressing IFN-β signalling and supporting pro-angiogenic signalling. This altered crosstalk converts normal fibroblasts into tumour-supporting cancer-associated fibroblasts with altered p53 functionality. The altered transcriptional program of cancer-associated fibroblasts (CAFs) supports pro-tumorigenic signalling and extracellular matrix remodelling. The demographic and functionality of infiltrating immune cells is consequently shifted to favour immunosuppression, ultimately leading to a chronically inflamed environment and enhanced migration and invasion.

Figure 3

Mutant p53 impacts on the immune and inflammatory hallmarks of cancer. Mutant p53 responds to and contributes to cancer-associated chronic inflammation which facilitates several immune gain-of-functions. These are highlighted by the mutant p53-mediated alteration of the tumour milieu (pro-invasive extracellular matrix structure, cancer-associated fibroblast activity, tumour-tolerant immune cell infiltrate and chemical signatures), disabling of the innate immune response through aberrant toll-like receptor signalling, the inhibition of cell-mediated cancer immunity and potentially disrupting post-apoptotic cell clearance.