title: Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment.
abstract: The tumor suppressorp53is 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 ofp53inactivation/dysfunction on tumorigenesis, compelling evidence suggests thatp53mutation/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 thatp53dysfunction 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 thatp53dysfunction 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Cancer Immunology, Inflammation & Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. ycui@augusta.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Biology, Cancer Immunology, Inflammation & Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. gguo@augusta.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Guo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D057131:Immune Evasion; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; D051193:Toll-Like Receptors; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: adaptive antitumor immunity; immune suppression; immunotherapy; inflammation; innate immunity; p53 inactivation; tumor microenvironment; tumor suppressor p53