Immune and chromosomal challenges, including DNA damage, figure prominently in the cause of cancer. A role of immunity goes back to the early 1900s when the origins of cancer were considered microbial and radiation treatment was thought to induce specific anticancer immune responses . How immuno-stress and chromosomal-stress responses can interact to enhance the likelihood of cancer remains an intriguing area of investigation.
The immune system is comprised of innate immunity that is an early, general attack system against infecting agents, and adaptive immunity that provides specific protection against a variety of agents. There are at least three ways in which immune responses protect the body from tumor formation. First, both adaptive and innate immunity can suppress viral infections that have the potential for direct cellular transformation . Second, immunosurveillance, which involves cooperation between both types of immunity, identifies and eliminates transformed cells before they can establish malignancy (for a review see [3▪▪]). Many tumor-associated antigens that generate antibody responses provide guidance systems for removal of emerging neoplastic cells. Immune depleted mice are highly cancer prone and multiple cancer types, especially those of infectious origin, are increased in immune-suppressed AIDS patients or solid transplant recipients . Third, pathogen removal by the immune system reduces opportunities for inflammation, which is also considered a source of cancer as well as of many other diseases. Chronic inflammation and autoimmunity are associated with the development of malignancy . However, once tumors are established, the inflammatory response changes and a set of immune cells that are immunomodulatory, rather than inflammatory, can enhance tumor progression and metastasis by promoting angiogenesis, enhancing cell migration, invasion and intravasation and suppressing antitumor immunity.
DNA damage, chromosomal alterations and mutations are sources of cancer. As a master regulator of choices between cell progression and death, the tumor-suppressor p53 figures prominently in reducing the impacts of chromosomal stress. Lately, there has been a merging of the concepts of suppression of cancer via innate immunity and suppression via monitoring of chromosomal stress. The Toll-like receptor proteins (TLRs), which provide front-line protection against pathogens through recognition of general features or pathogen-associated molecular patterns (PAMPs), assure rapid inflammatory responses as well as communications with adaptive immunity cells. Recently, we established a direct regulatory relationship between the inducible p53 and the innate immune pathway [6,7▪]. The expression of most TLR genes in human primary and cancer cells was directly affected by changes in p53. In this brief review, we discuss p53 and its relationship to the immune system with emphasis on innate immunity.
P53 AND INTERACTIONS WITH THE IMMUNE SYSTEM
The tumor suppressor p53 is a sequence-specific transcription factor that is a critical component in dealing with genome destabilizing events. In the absence of cellular stress, p53 proteins are present at low levels, mainly in the cytoplasm. In response to various stresses that include DNA damage, oncogene activation, virus infection and hypoxia, the half-life of p53 is greatly increased [8,9]. Because of stress-specific post-translation modifications p53 translocates into the nucleus and binds to specific DNA response element sequences wherein p53 regulates transcription of hundreds of genes involved in many biological functions.
Cell-cycle arrest and death are among the biological consequences that provide opportunities to eliminate chromosomal damage and damaged cells that could lead to cancer. Direct inactivation of p53 functions by mutations or deregulation in the p53 pathway is common in human cancers [8,10] with over 80–90% of tumors having an altered p53 pathway . Recently, p53 functions were extended to a wide range of biological activities such as fertility, programmed necrosis, aging, metabolism, differentiation and immunity .
Since the discovery of p53, there has been interest in the relationship between p53 and immune responses, especially in tumor immunology. To avoid reaction to self-antigens, immune systems distinguish self from nonself. The p53 program may provide an attractive option for immunotherapy as p53 that is present in tumor cells may be considered nonself [13,14]. It has been over 30 years since the identification of circulating antibodies against the human p53 in the sera of cancer patients [15,16]. Most p53 mutations are single amino acid alterations, many leading to extended half-life and accumulation in tumor cells whereas p53 is normally rapidly degraded [17–19]. Specific immune responses against wild type and mutant p53's are common in cancer patients and are employed in cancer diagnosis, prognosis and immunotherapy [20,21]. Several p53-based vaccines have proved effective in animal models and are undergoing human trials [22–25].
The interaction of p53 protein with oncoviral proteins as well as the presence of a specific immune response towards this protein in animals bearing chemical-induced and virus-induced tumors were key observations during early p53 research [26–30]. Several viral infections trigger activation of the p53 pathway (reviews by [31,32]), including adenovirus, influenza A virus, Epstein–Barr virus or HIV-1 infections [33–36]. In addition, p53 expression can be directly activated by type I interferon (IFN) in response to vesicular stomatitis virus infection . p53 also influences the antiviral response to influenza A virus (IAV) in a mouse model through its effects on both innate and adaptive immune responses [38▪▪].
Many viruses have evolved mechanisms that disrupt p53 functions either directly or through cellular factors involved in downstream activities by overriding cell-cycle checkpoints or by protecting cells from p53-dependent apoptosis. Viral oncoproteins such as SV40 large T antigen, human papilloma virus E6, adenovirus E1B-55K, human herpes virus 6 DR7, hepatitis B virus HBX, human T-cell leukemia virus type I Tax, Epstein–Barr virus BZLF1 and LMP1 block p53-dependent responses in infected cells and, in some cases, target p53 for proteasome degradation .
In addition to tumor suppression, there is a strong connection between p53 and the immune response suggesting that p53 also orchestrates responses to DNA damage by mediating innate immune system clearance of damaged cells [39,40]. For example, in mice with liver carcinomas, tumor regression through p53 reactivation is associated with upregulation of several proinflammatory cytokines and activation of innate immunity . Also, an extra copy of p53 in mice conveys viral immunity as well as decreased tumorigenesis . Using a humanized p53 knock-in (Hupki) mouse, a polymorphism in codon 72 of p53 was found to influence p53-mediated inflammatory responses through cooperation with NF-κB, a well known master regulator of immune and inflammatory responses [43▪▪].
The p53-dependent transcriptional program can increase expression of key regulators of immunity pathways, particularly innate immunity, and several direct target genes of p53 have been identified within pathways involved in pathogen sensing, cytokine production, and inflammation. A clear role of p53 transcriptional activities has been demonstrated in the host defense against viral infection and modulation of the type I IFN signaling. Included in this group are Toll-like receptors 3 and 8, IFN Regulatory Factors 5 and 9, IFN-stimulated gene 15 and dsRNA-activated protein kinase R. Additionally, p53 regulates the transcription of several cytokines and chemokines involved in innate immunity including colony-stimulating factor 1 and monocyte chemotactic protein 1, chemokine CXC motif ligand 1 and interleukin 15 (IL-15) that attract macrophages, neutrophils, and natural killer (NK) cells, contributing to immune elimination of senescent cells . p53 can also activate an antitumor immune response via direct transcriptional regulation of natural killer cell ligands ULBP1 and ULBP2 in cancer cells, [44,45] leading to enhanced NK-cell activation. Presented in Table 1 [6,7▪,41,44–55] are p53 targets involved in immune response.
TOLL-LIKE RECEPTORS AND P53
As for many cell types, activation of p53 in cells associated with the immune system can alter expression of many genes encoding apoptotic proteins, cell-cycle inhibitors, and inflammatory cytokines. The genes in the TLR pathway were generally considered to be hard-wired wherein changes in the pathways arise through TLR-signaling to downstream genes and proteins. Contrary to that view, we and others recently showed that several members of the TLR family are transcriptionally regulated by p53 in response to different stressors including DNA damage [6,55,56].
Our approach to identifying transcriptional control of p53 target genes through knowledge of potential p53-response elements led to the discovery of several TLR genes being responsive to p53. The sequence-specific DNA binding activity of p53 is critical to its tumor suppressor activity. p53 was considered to bind as a dimer-of-dimers to p53-response elements that consist of two consensus DNA binding sequences (5’-PuPuPuC(A/T)(T/A)GPyPyPy-3’) separated by a variable spacer [57,58]. Although many p53 target genes that contain p53-response elements in the promoter region have been identified, the selective transactivation mechanism is not well understood. Many factors affect p53 promoter binding, including post-translational modifications, cofactors and promoter DNA topology . In addition to this consensus, studies in yeast and human cells  established that tetrameric p53 protein is able to bind and mediate transactivation in vivo at half and three-quarter binding sequences and led to our establishing of ‘rules’ for predicting in-vivo functionality of p53 response elements. The rules include the impact of separation of decamers and the role of the core CWWG sequence (where W= A or T) (summarized in [59,60]).
Among several potential p53-response elements identified in silico, we found that nearly all members of the human TLR family tested (TLR1–10) have at least one canonical or noncanonical (half-site) p53 response element within ±5 kb of the transcription start site that is predicted to provide at least weak-to-modest p53 responsiveness. We demonstrated directly that chromosomal damage can affect the immune system by altering the expression of TLRs in primary cells from healthy individuals, confirming predictions about p53 control of TLR expression . When peripheral blood lymphocytes from 18 healthy individuals were treated with anticancer agents (Nutlin-3, ionizing radiation, fluorouracil, and doxorubicin), all genes encoding TLRs were responsive to DNA damage, and most expression changes were mediated by p53. Doxorubicin also induced several TLRs in primary human alveolar macrophages, albeit with a different profile for the specific TLRs, suggesting a cell-type specific response. The effects on TLR expression were associated with direct p53 binding to the predicted canonical and noncanonical p53-response elements. Upregulation of TLRs by chromosomal stressors had a functional outcome, influencing PAMP-induced TLR cytokine responses. Upregulation of TLR2 by the p53-specific activator drug Nutlin-3 in CD3+ lymphocytes resulted in a two-fold to five-fold increase in expression of IL-1 and IL-8 when cells were exposed to TLR2 ligand, demonstrating that TLR induction by p53 can affect innate immune function. Overall, these findings directly merged the TLR immune pathway with p53-determined DNA damage and stress responses in human primary cells. Presented in Fig. 1 is a p53 – TLR response loop describing how chromosomal stress could influence the immune response.
Surprisingly, the p53-mediated expression of TLRs appears to be unique to primates, based on phylogenetic analyses of p53-response elements in the TLR promoters. Consistent with a lack of p53-response elements, most TLR expression in mice is not influenced by DNA damage. This finding suggests that humans and their close relatives have evolved enhanced innate immune inflammatory responses that can respond to DNA damage.
Interestingly, we observed considerable variability between humans in TLR transcriptional responses to DNA damage and p53 induction. In addition, some individuals appeared to be high responders across all TLR genes and some were low responders. These findings suggest genetic variability that might dictate, in part, the magnitude of TLR responses to DNA damage and p53 activation. Possibly, some people are more prone to inflammation following DNA damage, such as after receiving cancer therapy.
Similar to primary cells, activation of p53 can alter expression of TLRs in cancer cell lines and lead to increased ligand-mediated expression of cytokines downstream of the corresponding TLR. The responses of individual TLR genes (in most cases, increases) differ between cell lines, genotoxic treatments (doxorubicin, 5-fluorouracil (5-FU), ionizing radiation), pharmacological stabilization (Nutlin-3) and p53-overexpression. Therefore, profiling the changes in TLR gene expression in tumors and tumor-associated immune cells in response to DNA damaging and p53-inducing agents could be a useful tool in strategies that utilize TLRs for cancer therapy, as discussed below.
SINGLE NUCLEOTIDE POLYMORPHISM IN TOLL-LIKE RECEPTOR 8 RESPONSE ELEMENT CHANGES P53 RESPONSIVENESS
Especially intriguing was p53 induction of TLR8 wherein a single nucleotide polymorphism (SNP) markedly altered the response. Several years ago, an in-silico search of the available SNP database suggested that p53 may have a role in expression of human TLR8. A SNP (ChrX:12923681, rs3761624 A/G) in the promoter creates an response element that could be specifically targeted by p53 in yeast and human cell reporters . (p53 response element sequence SNPs in the response elements of TLR5 and TLR6 were predicted to have no functional impact on the expression of those genes.) The impact of the polymorphism was not clear as in the cancer cell lines studied there was no endogenous TLR8 expression. However, using primary human lymphocytes as well as alveolar macrophages, we confirmed that the TLR8 promoter SNP indeed affects the expression of this gene in a treatment-specific manner.
The ability of Nutlin-3 and ionizing radiation to induce TLR8 in primary cells correlated well with the presence of the G-allele which creates a highly responsive CATG core in the p53 binding sequence (AAACAT(G/A)TCa), but not with the presence of the A-allele. The TLR8 gene is located on the X-chromosome so that p53-induced expression at TLR8 was always high when only G-alleles were present (both alleles in women or the single allele in men) and absent if there was only the A-allele. Treatment with 5-FU or doxorubicin did not alter the expression of TLR8 in primary cells suggesting that other p53-related target sequences might be responsible for the induction or involvement of additional p53-independent mechanisms. Overall, this variability in the TLR responses may be relevant to individual susceptibility to a wide spectrum of diseases and therapies. These findings also provide the first evidence in humans of transcription being driven by p53 at a specific response element.
THE INFLUENCE OF P53 MUTANTS ON TOLL-LIKE RECEPTOR EXPRESSION
Most cancer-associated p53 mutations are missense and are found within the central core DNA binding domain of the protein. Approximately, one-third of mutants retain transactivation capability and many exhibit change-in-spectrum in terms of transactivation from various p53 targets [61–64]. The change-in-spectrum mutants are expected to differentially alter gene expression resulting in altered cellular responses including DNA repair, replication, genome stability and programmed cell death [61,63]. We recently showed in a human p53-null cancer cell model that p53 mutants identified in somatic and germline-associated tumors can dramatically influence stress-induced gene expression of TLRs [7▪]. The patterns included change-of-spectrum in the induction/repression of target TLRs, although classic loss-of-function mutants did not affect TLR induction. Their impacts on cytokine and chemokine production after TLR activation by cognate ligands remains to be assessed. Mutants that might alter the efficacy of chemotherapeutic agents and diversify cell stress responses  could also influence downstream innate immune signaling.
Having established that wild-type and p53 mutants can modulate TLR expression differentially, we have proposed [7▪] that manipulation of normal or mutant p53 responses along with immune challenges that include TLRs or other novel targets such as ULBP2 in Table 1 could enhance inflammatory and immune type responses, as described in Fig. 1. Pharmacological restoration of the frequent loss-of-function p53 cancer mutants is an anticancer strategy  that could be employed along with activation. Several p53-reactivating chemicals including Nutlin-3a, PRIMA-1, RITA and tenovins have been identified and some are in Phase I clinical trials [20,66,67]. Along this line, pharmacological reactivation of p53 enhanced NK cell-mediated killing of cancer cells derived from patients with metastatic tumors of different origin as well as established cancer cell lines . Also, a strategy for immunomodulation of TLRs and activation p53 was recently reported .
USE OF TOLL-LIKE RECEPTOR LIGANDS IN CANCER THERAPY
In addition to activation of the innate immune system, TLR stimulation can be employed in cancer therapy to increase immune responses to tumor antigens and as an adjuvant in chemotherapy. For example, attenuated Bacillus Calmette–Guérin (BCG) has been used for years in bladder cancer treatments. Also, TLR immunotherapy, which is being widely developed, can have a more direct effect on cancer cells, affecting growth and viability (see review [69▪▪] and [70–72]). The TLR7 agonist Imiquimod is used to treat basal cell and cutaneous malignancies, and synthetic oligodeoxynucleotides containing unmethylated CpG motifs that activate TLR9 are being tested in clinical trials [73–75].
Having established a strong relationship between p53 and TLRs, we suggest that p53 activation could further enhance TLR-based human cancer therapies, although there are examples of TLR stimulation increasing cancer cell growth and survival [76,77]. Expression of TLR3, which was shown to induce apoptosis in cancer cells [71,72,78], is also induced by genotoxic agents across nearly all cell lines in a strictly p53-dependent manner. A combination of TLR3 ligand with genotoxic drugs could be especially beneficial for treatment of p53-positive tumors. Unlike TLR3, genotoxic stress increases TLR9 expression independent of p53 status, implying opportunities for combinations of genotoxins and TLR ligands in cancer treatments.
The relationship between immune responses and the tumor suppressor p53 provides unique opportunities for cancer therapies and other disease interventions as well. The p53-TLR interaction could be exploited to understand and possibly address diseases other than cancer, such as inflammatory bowel disease. Importantly, findings of human variability in the p53-TLR interaction would support individualized medicine approaches wherein ex-vivo responses could increase predictability. Manipulation of TLR signaling in cancer therapy must take into account possible opposing effects of TLR activation on tumor cells as well as on the tumor microenvironment (see review [69▪▪]). Overall, a profile of TLR gene expression in specific tumors in response to p53 and DNA damaging agents combined with knowledge of p53 expression and mutation status in these tumors can be an important tool in cancer diagnosis and in strategies using specific TLR agonists or antagonists that could target TLR pathways for cancer therapy.
We thank Dr Michael B. Fessler and Dr Julie Lowe for comments on the manuscript. Support was provided by NIEHS intramural research funds, project Z01-ES065079, to M.A.R., D.M. and M.S.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 102).
1. Hernaman-Johnson F. The use of X Rays as immunity-raising agents before and after operation for cancer. Br Med J 1920; 1:793–795.
2. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011; 29:235–271.
3▪▪. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:1565–1570.
An excellent review discussing the concept of ‘cancer immunoediting’ and analysing the dual role of immune systems in cancer progression
4. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59–67.
5. Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 2012; 32:1119–1136.
6. Menendez D, Shatz M, Azzam K, et al. The toll-like receptor gene family is integrated into human DNA damage
networks. PLoS Genet 2011; 7:e1001360.
7▪. Shatz M, Menendez D, Resnick MA. The human TLR innate immune gene family is differentially influenced by DNA stress and p53
status in cancer cells. Cancer Res 2012. [Epub ahead of Print].
Demonstrates a novel role for p53 as a modulator of TLR genes expression and function in cancer cells and suggests a potential significance in cancer therapy.
8. Vogelstein B, Lane D, Levine AJ. Surfing the p53
network. Nature 2000; 408:307–310.
9. Lane D, Levine A. p53
Research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol 2010; 2:a000893.
10. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53
functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007; 28:622–629.
11. Soussi T. The history of p53
. A perfect example of the drawbacks of scientific paradigms. EMBO Rep 2010; 11:822–826.
12. Levine AJ. Introduction: the changing directions of p53
research. Genes Cancer 2011; 2:382–384.
13. Lauwen MM, Zwaveling S, de Quartel L, et al. Self-tolerance does not restrict the CD4+ T-helper response against the p53
tumor antigen. Cancer Res 2008; 68:893–900.
14. DeLeo AB. p53
-based immunotherapy of cancer. Crit Rev Immunol 1998; 18:29–35.
15. Caron de Fromentel C, May-Levin F, Mouriesse H, et al. Presence of circulating antibodies against cellular protein p53
in a notable proportion of children with B-cell lymphoma. Int J Cancer 1987; 39:185–189.
16. Crawford LV, Pim DC, Bulbrook RD. Detection of antibodies against the cellular protein p53
in sera from patients with breast cancer. Int J Cancer 1982; 30:403–408.
17. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53
mutations in human cancers. Science 1991; 253:49–53.
18. Zambetti GP, Levine AJ. A comparison of the biological activities of wild-type and mutant p53
. FASEB J 1993; 7:855–865.
19. Dowell SP, Wilson PO, Derias NW, et al. Clinical utility of the immunocytochemical detection of p53
protein in cytological specimens. Cancer Res 1994; 54:2914–2918.
20. Lane DP, Cheok CF, Lain S. p53
-based cancer therapy
. Cold Spring Harb Perspect Biol 2010; 2:a001222.
21. Vermeij R, Leffers N, van der Burg SH, et al. Immunological and clinical effects of vaccines targeting p53
-overexpressing malignancies. J Biomed Biotechnol 2011; 2011:702146.
22. Sakakura K, Chikamatsu K, Furuya N, et al. Toward the development of multiepitope p53
cancer vaccines: an in vitro assessment of CD8(+) T cell responses to HLA class I-restricted wild-type sequence p53
peptides. Clin Immunol 2007; 125:43–51.
23. Chiappori AA, Soliman H, Janssen WE, et al. INGN-225: a dendritic cell-based p53
-DC) in small cell lung cancer – observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther 2010; 10:983–991.
24. Speetjens FM, Kuppen PJ, Welters MJ, et al. Induction of p53
-specific immunity by a p53
synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res 2009; 15:1086–1095.
25. Hoffmann TK, Donnenberg AD, Finkelstein SD, et al. Frequencies of tetramer+ T cells specific for the wild-type sequence p53
(264-272) peptide in the circulation of patients with head and neck cancer. Cancer Res 2002; 62:3521–3529.
26. DeLeo AB, Jay G, Appella E, et al. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 1979; 76:2420–2424.
27. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278:261–263.
28. Melero JA, Stitt DT, Mangel WF, Carroll RB. Identification of new polypeptide species (48-55K) immunoprecipitable by antiserum to purified large T antigen and present in SV40-infected and -transformed cells. Virology 1979; 93:466–480.
29. Rotter V, Witte ON, Coffman R, Baltimore D. Abelson murine leukemia virus-induced tumors elicit antibodies against a host cell protein. P50 J Virol 1980; 36:547–555.
30. Soussi T. p53
Antibodies in the sera of patients with various types of cancer: a review. Cancer Res 2000; 60:1777–1788.
31. Collot-Teixeira S, Bass J, Denis F, Ranger-Rogez S. Human tumor suppressor p53
and DNA viruses. Rev Med Virol 2004; 14:301–319.
32. Rivas C, Aaronson SA, Munoz-Fontela C. Dual role of p53
in innate antiviral immunity. Viruses 2010; 2:298–313.
33. Genini D, Sheeter D, Rought S, et al. HIV induces lymphocyte apoptosis by a p53
-initiated, mitochondrial-mediated mechanism. FASEB J 2001; 15:5–6.
34. Kraljevic Pavelic S, Marjanovic M, Poznic M, Kralj M. Adenovirally mediated p53
overexpression diversely influence the cell cycle of HEp-2 and CAL 27 cell lines upon cisplatin and methotrexate treatment. J Cancer Res Clin Oncol 2009; 135:1747–1761.
35. Sato Y, Shirata N, Murata T, et al. Transient increases in p53
-responsible gene expression at early stages of Epstein-Barr virus productive replication. Cell Cycle 2010; 9:807–814.
36. Turpin E, Luke K, Jones J, et al. Influenza virus infection increases p53
activity: role of p53
in cell death and viral replication. J Virol 2005; 79:8802–8811.
37. Takaoka A, Hayakawa S, Yanai H, et al. Integration of interferon-alpha/beta signalling to p53
responses in tumour suppression and antiviral defence. Nature 2003; 424:516–523.
38▪▪. Munoz-Fontela C, Pazos M, Delgado I, et al. p53
serves as a host antiviral factor that enhances innate and adaptive immune responses to influenza A virus. J Immunol 2011; 187:6428–6436.
Postulates a novel function of p53 as an antiviral factor that facilitates immune responses. Shows that p53 is required for timely expression of antiviral genes and proinflammatory cytokines and viral clearance in Influenza A virus-infected mice.
39. Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53
restoration in tumors. Cell 2006; 127:1323–1334.
40. Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53
function leads to tumour regression in vivo. Nature 2007; 445:661–665.
41. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53
restoration in murine liver carcinomas. Nature 2007; 445:656–660.
42. Munoz-Fontela C, Garcia MA, Garcia-Cao I, et al. Resistance to viral infection of super p53
mice. Oncogene 2005; 24:3059–3062.
43▪▪. Frank AK, Leu JI, Zhou Y, et al. The codon 72 polymorphism of p53
regulates interaction with NF-kB and transactivation of genes involved in immunity and inflammation. Mol Cell Biol 2011; 31:1201–1213.
Novel and unexpected finding of transcriptional and functional interaction between the tumor supressor p53 and NF-kappaB
44. Li H, Lakshmikanth T, Garofalo C, et al. Pharmacological activation of p53
triggers anticancer innate immune response
through induction of ULBP2. Cell Cycle 2011; 10:3346–3358.
45. Textor S, Fiegler N, Arnold A, et al. Human NK cells are alerted to induction of p53
in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res 2011; 71:5998–6009.
46. Kadaja-Saarepuu L, Looke M, Balikova A, Maimets T. Tumor suppressor p53
down-regulates expression of human leukocyte marker CD43 in nonhematopoietic tumor cells. Int J Oncol 2012; 40:567–576.
47. Shiraishi K, Fukuda S, Mori T, et al. Identification of fractalkine, a CX3C-type chemokine, as a direct target of p53
. Cancer Res 2000; 60:3722–3726.
48. Gorgoulis VG, Zacharatos P, Kotsinas A, et al. p53
activates ICAM-1 (CD54) expression in an NF-kappaB-independent manner. EMBO J 2003; 22:1567–1578.
49. Mori T, Anazawa Y, Iiizumi M, et al. Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53
. Oncogene 2002; 21:2914–2918.
50. Munoz-Fontela C, Macip S, Martinez-Sobrido L, et al. Transcriptional role of p53
in interferon-mediated antiviral immunity. J Exp Med 2008; 205:1929–1938.
51. Hummer BT, Li XL, Hassel BA. Role for p53
in gene induction by double-stranded RNA. J Virol 2001; 75:7774–7777.
52. Hacke K, Rincon-Orozco B, Buchwalter G, et al. Regulation of MCP-1 chemokine transcription by p53
. Mol Cancer 2010; 9:82.
53. Yoon CH, Lee ES, Lim DS, Bae YS. PKR, a p53
target gene, plays a crucial role in the tumor-suppressor function of p53
. Proc Natl Acad Sci U S A 2009; 106:7852–7857.
54. Iwaki S, Lu Y, Xie Z, Druey KM. p53
negatively regulates RGS13 protein expression in immune cells. J Biol Chem 2011; 286:22219–22226.
55. Taura M, Eguma A, Suico MA, et al. p53
regulates Toll-like receptor 3 expression and function in human epithelial cell lines. Mol Cell Biol 2008; 28:6557–6567.
56. Tomso DJ, Inga A, Menendez D, et al. Functionally distinct polymorphic sequences in the human genome that are targets for p53
transactivation. Proc Natl Acad Sci U S A 2005; 102:6431–6436.
57. el-Deiry WS, Kern SE, Pietenpol JA, et al. Definition of a consensus binding site for p53
. Nat Genet 1992; 1:45–49.
58. Funk WD, Pak DT, Karas RH, et al. A transcriptionally active DNA-binding site for human p53
protein complexes. Mol Cell Biol 1992; 12:2866–2871.
59. Menendez D, Inga A, Resnick MA. The expanding universe of p53
targets. Nat Rev Cancer 2009; 9:724–737.
60. Jordan JJ, Menendez D, Inga A, et al. Noncanonical DNA motifs as transactivation targets by wild type and mutant p53
. Plos Genetics 2008; 4:e1000104.
61. Resnick MA, Tomso D, Inga A, et al. Functional diversity in the gene network controlled by the master regulator p53
in humans. Cell Cycle 2005; 4:1026–1029.
62. Kato S, Han SY, Liu W, et al. Understanding the function-structure and function-mutation relationships of p53
tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A 2003; 100:8424–8429.
63. Menendez D, Inga A, Resnick MA. The biological impact of the human master regulator p53
can be altered by mutations that change the spectrum and expression of its target genes. Mol Cell Biol 2006; 26:2297–2308.
64. Jordan JJ, Inga A, Conway K, et al. Altered-function p53
missense mutations identified in breast cancers can have subtle effects on transactivation. Mol Cancer Res 2010; 8:701–716.
65. Temam S, Flahault A, Perie S, et al. p53
gene status as a predictor of tumor response to induction chemotherapy of patients with locoregionally advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2000; 18:385–394.
66. Brooks CL, Gu W. New insights into p53
activation. Cell Res 2010; 20:614–621.
67. Selivanova G. Therapeutic targeting of p53
by small molecules. Semin Cancer Biol 2010; 20:46–56.
68. Favaro WJ, Nunes OS, Seiva FR, et al. Effects of P-MAPA immunomodulator on toll-like receptors
: potential therapeutic strategies for infectious diseases and cancer. Infect Agent Cancer 2012; 7:14.
69▪▪. Goutagny N, Estornes Y, Hasan U, et al. Targeting pattern recognition receptors in cancer immunotherapy. Target Oncol 2012; 7:29–54.
An extensive review covering the use of TLR ligands in tumor therapy and context-dependent protumoral or antitumoral effect of the treatment.
70. Garay RP, Viens P, Bauer J, et al. Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur J Pharmacol 2007; 563:1–17.
71. Salaun B, Coste I, Rissoan MC, et al. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 2006; 176:4894–4901.
72. Taura M, Fukuda R, Suico MA, et al. TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis. Cancer Sci 2010; 101:1610–1617.
73. Bong AB, Bonnekoh B, Franke I, et al. Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 2002; 205:135–138.
74. Geisse J, Caro I, Lindholm J, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50:722–733.
75. Krieg AM. Development of TLR9 agonists for cancer therapy
. J Clin Invest 2007; 117:1184–1194.
76. Cherfils-Vicini J, Platonova S, Gillard M, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 2010; 120:1285–1297.
77. Kelly MG, Alvero AB, Chen R, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 2006; 66:3859–3868.
78. Paone A, Starace D, Galli R, et al. Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis 2008; 29:1334–1342.