New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy

Journal for ImmunoTherapy of Cancer

Yan Cui¹  Gang Guo¹ 

[1]Department of Biochemistry and Molecular Biology, Cancer Immunology, Inflammation & Tolerance Program, Georgia Regents University Cancer Center, Augusta 30912, GA, USA

关键词: Immunotherapy;    Antitumor immunity;    Inflammation;    Immune suppression;    Tumor microenvironment;    p53 inactivation;    Tumor suppressor p53;    Cancer;   

Others  :  1144128
DOI  :  10.1186/s40425-015-0053-5

 received in 2014-08-26, accepted in 2015-02-26,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Guo and Cui; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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