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Review
. 2016 Nov 19;17(11):1942.
doi: 10.3390/ijms17111942.

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Yan Cui  1 , Gang Guo  2
Affiliations
Review

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Yan Cui et al. Int J Mol Sci. .

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.

Keywords: adaptive antitumor immunity; immune suppression; immunotherapy; inflammation; innate immunity; p53 inactivation; tumor microenvironment; tumor suppressor p53.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular constituents of the tumor microenvironment that shape tumor immunological landscape. The tumor microenvironment consists of complex cellular and molecular and constituents. The cellular constituents consist of immune cells of hematopoietic origin and stromal cells of non-hematopoietic origin. The immune cell compartment comprises tumor-infiltrating lymphocytes of T, B, and natural killer cells and tumor-associated myeloid populations of dendritic cells, macrophages, and myeloid-derived suppressor cells. The stromal compartment consists of cancer-associated fibroblasts and endothelial cells of the lymphatic and blood vasculature. Trp53 inactivation has been observed in some of the cellular subpopulations of the tumor microenvironment, which compromises the proper balance of host immunity by promoting chronic inflammation and tumor progression.
Figure 2
Figure 2
Targeting the p53 pathway in the tumor microenvironment (TME) to activate antitumor immunity for systemic tumor control. Local activation of the p53 pathway in the TME can be achieved via intratumoral injection of specific p53 activators (A). This induces tumor immunogenic cell death and subsequent activation of macrophages and dendritic cells at confined areas around the site of injection. Activated macrophages and DCs update and present tumor antigens to activate T cells that kill more tumor cells (A). This T cell-mediated tumor killing further amplifies the activation events of macrophages, DCs, and T cells that execute and expand tumor killing around the injection site (B). Importantly, activated T cells travel in circulation through blood and lymphatic vasculatures to find and kill additional tumors distal to the site of injection (B). Activated systemic adaptive immunity via local p53 activation in the TME supports systemic tumor control and regression. CAF: cancer-associated fibroblasts.
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