Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment.
Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment.
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DOI：
10.3390/ijms17111942
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发表时间：
2016-11-19
影响因子：
5.6
通讯作者：
Guo G
中科院分区：
文献类型：
--
作者：
Cui Y;Guo G
肿瘤抑制基因p53是人类癌症中最常见的突变基因。大多数突变是错义的，导致p53在诱导细胞凋亡和衰老中的功能丧失。除了p53失活/功能障碍对肿瘤发生的这些自主作用之外，令人信服的证据表明，p53突变/失活还导致功能获得或非自主途径的激活，这直接或间接地促进肿瘤发生。实验和临床结果表明，p53功能障碍促进促肿瘤炎症，并通过扭曲肿瘤微环境（TME）的免疫景观作为肿瘤发生的免疫功能获得驱动因素。现在越来越多地认识到，TME的各种细胞区室中的p53功能障碍导致免疫抑制和免疫逃避。虽然我们对p53活性与宿主免疫调节之间的细胞和分子过程的理解仍然不完全，但很明显，激活/再激活TME中的p53通路也代表了一种令人信服的免疫策略，可以逆转免疫抑制并增强抗肿瘤免疫力。在这里，我们回顾了我们目前对p53参与免疫调节的潜在细胞和分子机制的理解，并讨论了如何利用靶向p53通路来改变肿瘤的免疫学景观，以最大限度地提高治疗效果。
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.
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