New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy.
New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy.
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DOI：
10.1186/s40425-015-0053-5
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发表时间：
2015
影响因子：
10.9
通讯作者：
Cui Y
中科院分区：
文献类型：
--
作者：
Guo G;Cui Y
约50%的人类癌症具有肿瘤抑制基因p53（p53或Trp53）的体细胞突变。这些突变中的许多导致p53途径的失活，并且通常与突变型p53蛋白的稳定和积累相关。因此，肿瘤中增加的p53表达经常被用作p53突变和失活的替代标志物。此外，这种升高的p53表达也使其成为癌症疫苗的理想肿瘤相关抗原（TAA）。最近的进展，我们的理解p53作为一个关键的转录因子显示，p53是一个重要的传感器的细胞应激基因毒性，化学毒性，病理，甚至正常的生理条件下。我们实验室和其他人的实验和临床观察表明，p53也参与免疫调节，因为p53功能障碍使宿主免疫反应偏向促炎症，这进一步促进肿瘤进展。此外，最近使用遗传方法的研究表明，p53恢复或重新激活会导致肿瘤消退和清除，这至少部分是由先天抗肿瘤免疫的激活引起的。由于目前使用的许多癌症治疗方法，包括放疗和化疗，通过基因毒性或化学毒性应激诱导DNA损伤来破坏肿瘤生长，这激活了肿瘤微环境中的p53通路，我们假设一些观察到的治疗益处也可能部分通过其免疫刺激作用介导。在这里，我们简要回顾了我们目前对p53参与免疫调节的潜在细胞和分子机制的理解，随后，将我们的讨论扩展到现有的和新的靶向p53通路的免疫刺激潜力，以改变肿瘤的免疫景观，从而最大限度地提高免疫治疗效果。
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.
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影响因子：
4
作者：
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通讯作者：
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影响因子：
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