RT Journal Article
SR Electronic
T1 New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 9
DO 10.1186/s40425-015-0053-5
VO 3
IS 1
A1 Gang Guo
A1 Yan Cui
YR 2015
UL http://jitc.bmj.com/content/3/1/9.abstract
AB About 50% of human cancers harbor somatic mutations of the tumor suppressor p53 (p53 or Trp53) gene. Many of those mutations result in the inactivation of the p53 pathway and are often associated with the stabilization and accumulation of mutant p53 proteins. Therefore, increased p53 expression in tumors is frequently used as a surrogate marker for p53 mutation and inactivation. Moreover, this elevated p53 expression also makes it an ideal tumor associated antigen (TAA) for cancer vaccines. Recent advances in our understanding of p53 as a crucial transcription factor reveal that p53 is an important sensor of cellular stress under genotoxic, chemotoxic, pathological, and even normal physiological conditions. Experimental and clinical observations by our laboratory and others have demonstrated that p53 also participates in immune regulation as p53 dysfunction skews host immune responses towards pro-inflammation, which further promotes tumor progression. Furthermore, recent studies using a genetic approach revealed that p53-restoration or re-activation led to tumor regression and clearance, which were at least partially caused by the activation of innate antitumor immunity. Since many of the currently used cancer therapeutics, including radiotherapy and chemotherapy, disrupt tumor growth by inducing DNA damage via genotoxic or chemotoxic stress, which activates the p53 pathway in the tumor microenvironment, we postulate that some of those observed therapeutic benefits might also be partially mediated through their immune stimulatory effects. Here, we briefly review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and, subsequently, extend our discussion to the immunostimulatory potential of existing and new approaches of targeting the p53-pathway to alter the immunological landscape of tumors for maximizing immunotherapy outcome.Abbreviations:Trp53p53, Transformation-related protein 53, tumor suppressor p53TAATumor associated antigenTMETumor microenvironmentMDM2Mouse double minute 2 homologSCO2Synthesis of cytochrome c oxidaseTIGARTP53-induced glycolysis and apoptosis regulatorDRAMDamage regulated autophagy mediatorAMPKAMP-activated protein kinaseEMTEpithelial to mesenchymal transitionCAFCancer associated fibroblastsAICDActivation-induced cell deathMDSCMyeloid derived suppressor cellSTATSignal transducers and activators of transcriptionHMGB1High-mobility group box 1ICDImmunogenic cell deathIRFInterferon regulatory factorISGFInterferon stimulated gene factorRITAReactivation of p53 and induction of tumor cell apoptosisPRIMA-1P53 reactivation and induction of massive apoptosis-1MIRA-3Mutant p53 reactivation and induction of rapid apoptosis