Abstract
The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence suggests that p53 mutation/inactivation also leads to gain-of-function or activation of non-autonomous pathways, which either directly or indirectly promote tumorigenesis. Experimental and clinical results suggest that p53 dysfunction fuels pro-tumor inflammation and serves as an immunological gain-of-function driver of tumorigenesis via skewing immune landscape of the tumor microenvironment (TME). It is now increasingly appreciated that p53 dysfunction in various cellular compartments of the TME leads to immunosuppression and immune evasion. Although our understanding of the cellular and molecular processes that link p53 activity to host immune regulation is still incomplete, it is clear that activating/reactivating the p53 pathway in the TME also represents a compelling immunological strategy to reverse immunosuppression and enhance antitumor immunity. Here, we review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and discuss how targeting the p53 pathway can be exploited to alter the immunological landscape of tumors for maximizing therapeutic outcome.
Highlights
The tumor suppressor p53, as a crucial transcription factor controlling the life and death of cells, has been known to prevent tumorigenesis via inducing apoptosis and senescence [1,2,3,4]
These results suggest that while p53 mutation/inactivation can be induced by environmental stress and tissue inflammation, the resulting inactivation of the p53 pathway in epithelial cells further amplifies chronic inflammation in the tumor microenvironment (TME) that likely promotes a vicious cycle of altered immunological milieu that promotes tumor progression and metastasis
Because Th17/IL-17 activity has been linked to inflammation, autoimmunity, and tumorigenesis [78,79,80], these results verify that p53 inactivation in immune cells augments inflammation-induced tumorigenesis via multiple pathways, such as enhancing production of inflammatory cytokines and chemokines, promoting the differentiation and function of Th17 cells, and suppressing the differentiation of Treg
Summary
The tumor suppressor p53, as a crucial transcription factor controlling the life and death of cells, has been known to prevent tumorigenesis via inducing apoptosis and senescence [1,2,3,4]. It is noteworthy that this p53 inactivation-mediated gain of immunosuppressive function is not restricted to p53 deletion because the mouse model of p53 mutation, which mimics human hotspot p53 mutations, exemplifies exacerbated tissue inflammation in intestinal epithelial cells, liver, and breast tissues, leading to the development of colon, liver, and breast cancers, respectively [53,54,55] These results suggest that while p53 mutation/inactivation can be induced by environmental stress and tissue inflammation, the resulting inactivation of the p53 pathway in epithelial cells further amplifies chronic inflammation in the TME that likely promotes a vicious cycle of altered immunological milieu that promotes tumor progression and metastasis. This p53 inactivation-induced inflammatory capacity of epithelial cells is likely a result of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-mediated production of inflammatory cytokines, which is discussed in the molecular mechanism section
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