Tumor suppressor p53, known as 'the guardian of the genome', has the ability to prevent the emergence of transformed cells by the induction of cell cycle arrest and apoptosis. Otherwise, there were researches about the function of p53, such as NDA repair, regulating metabolism and maternal reproduction in recent years. Furthermore, there was a new function for p53 in antiviral apoptosis mentioned in the research, Integration of interferon-alpha/beta signaling to p53 responses in tumour suppression and antiviral defense. In order to define the antiviral function of p53, many target genes has been defined, such as IRF9, IRF5, ISG15 and TLR3. All of these implied there must be a complex mechanism for role of p53 in antiviral innate immunity, adaptive immunity and inflammation.
Animals ; Cell Physiological Phenomena ; Humans ; Immunity ; Inflammation ; immunology ; metabolism ; virology ; Tumor Suppressor Protein p53 ; genetics ; metabolism ; Viruses ; immunology

Actins ; immunology ; metabolism ; Antibodies, Monoclonal ; analysis ; Antigens, CD34 ; immunology ; metabolism ; Breast Neoplasms ; metabolism ; Female ; Humans ; Immunohistochemistry ; methods ; Lung Neoplasms ; metabolism ; Membrane Proteins ; immunology ; metabolism ; Tumor Suppressor Protein p53 ; immunology ; metabolism

Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database (TSNAdb v1.0), based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen (HLA) allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA). We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients, which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy. TSNAdb is freely available at http://biopharm.zju.edu.cn/tsnadb.
Antigens, Neoplasm ; metabolism ; Data Analysis ; Databases, Genetic ; Humans ; Immunotherapy ; Mutation ; genetics ; Neoplasms ; genetics ; immunology ; Tumor Suppressor Protein p53 ; genetics ; Urinary Bladder Neoplasms ; genetics

To investigate the effects of dendritic cells (DCs) transfected with full length wild type p53 and modified by gastric cancer lysates on immune response, the wild type P53 was transducted to DCs with adenovirus, and the DCs were modified by gastric cancer lysates (Lywt-P53DC). The concentration of the surface molecules (B7-1, B7-2, MHC-I , MHC-II) of all DCs was determined by FACS, and the ability of the DCs to induce efficient and specific immunological response in anti-51Cr-labeled target cells studied. BALB/c mice model infected with DCs and Mk28 was established. CTL response in mice immunized with Lywt-p53DC and the effectiveness of Lywt-p53DC in the treatment of tumor-bearing mice was assayed. FACS revealed that the surface molecules of Ly-wt-P53 DC had a high expression: for B7-1 86.70% +/- 0.07%, B7-2 18.77% +/- 0.08%, MHC-I 87.20% +/- 0.05%, MHC-II 56.70%+/-0.07%; The T lymphocytes had a specific CTL lysing ability induced by Lywt-P53DC with the CTL lysis rate being 81%. The immune protective effect of Lywt-p53DC group was more obvious than any other groups (P<0.05). The tumor diameter in Lywt-p53DC group was 3.10+/-0.31 mm, 2.73+/-0.23 mm, 3.70+/-0.07 mm on the day 13, 16 and 19, smaller than DC, wtp53DC and LyDC groups (P<0.05). On the other hand, the growth rate of tumor in Lywt-p53DC group was slower than any other groups (P<0.05). It was suggested that DCs transfected with wild type P53 and modified by gastric cancer lysates had specific CTL killing capability.
Adenoviridae ; genetics ; metabolism ; Animals ; Cell Line, Tumor ; Dendritic Cells ; immunology ; metabolism ; Female ; Genetic Vectors ; Mice ; Mice, Inbred BALB C ; Recombinant Proteins ; biosynthesis ; genetics ; Stomach Neoplasms ; immunology ; pathology ; T-Lymphocytes, Cytotoxic ; immunology ; Transfection ; Tumor Suppressor Protein p53 ; biosynthesis ; genetics

Germ-line mutations in BRCA2 predispose to early-onset cancer. Homozygous mutant mouse, which has Brca2 truncated in exon 11 exhibit paradoxic occurrence of growth retardation and development of thymic lymphomas. However, due to its large embryonic lethality, cohort studies on the thymic lymphomas were not feasible. With the aid of Cre-loxP system, we demonstrate here that thymus-specific disruption of Brca2 allele without crossing it to p53-mutant background leads to the development of thymic lymphomas. Varying from 16 weeks to 66 weeks after birth, 25% of mice disrupted of Brca2 in the thymus died of thymic lymphomas, whereas previous report did not observe lymphomagenesis using similar Cre-loxP system. Future analysis of thymic lymphomas from these mice presented here will provide information on the cooperative mutations that are required for the BRCA2-associated pathogenesis of cancer.
Animals ; BRCA2 Protein/deficiency/*genetics ; CD4-CD8 Ratio ; Cell Separation ; Flow Cytometry ; Integrases/*genetics/immunology ; Lymphoma/*genetics/immunology/metabolism/pathology ; Mice ; Mice, Knockout ; Organ Specificity ; *Sequence Deletion ; T-Lymphocytes/enzymology/*immunology ; Thymus Gland/immunology/metabolism/pathology ; Thymus Neoplasms/*genetics/immunology/metabolism/pathology ; Tumor Suppressor Protein p53/deficiency/genetics/immunology

In carcinoma ex pleomorphic adenoma (CXPA), pleomorphic adenoma (PA) and diverse carcinoma components showing luminal (ductal) or non-luminal (myoepithelial) differentiation coexist. To elucidate the clinicopathological implications of cellular differentiation in CXPA and the potential role of p53, vascular endothelial growth factor (VEGF), c-erbB-2, c-kit, and glucose transporter 1 (Glut-1) in carcinogenesis, we analyzed 11 CXPAs with luminal differentiation (CXPAs-LD) and 6 CXPAs with non-luminal differentiation (CXPAs-NLD) and compared protein expressions in residual PAs and carcinomas by immunohistochemistry. Among the CXPAs-LD, 5 were invasive and 8 were histologically high-grade tumors. The 5-year survival rate was 72.7%. P53, c-erbB-2, VEGF, and Glut-1 were more immunoreactive in carcinoma components than in PAs (P = 0.008, 0.004, 0.002, and 0.024, respectively); c-erbB-2 overexpression was associated with high histological grade (P = 0.024). Carcinoma components frequently lacked c-kit expression (P = 0.009). CXPAs-NLD were all low-grade and invasive with a larger mean tumor size (5.2 cm) than CXPAs-LD (3.3 cm) (P = 0.040). The patients remained disease-free without significant immunohistochemical expression. The immunoprofiles and clinical course of CXPA differed according to cellular differentiation. Therefore, it is important to report the histological subtype and to assess potential biomarkers in diagnostic and therapeutic trials.
Adenoma, Pleomorphic/*immunology/metabolism/*pathology ; Adult ; Aged ; Carcinoma/*immunology/metabolism/*pathology ; Cell Differentiation ; Female ; Glucose Transport Proteins, Facilitative/metabolism ; Humans ; Male ; Middle Aged ; Proto-Oncogene Proteins c-kit/metabolism ; Receptor, erbB-2/metabolism ; Salivary Gland Neoplasms/*immunology/metabolism/*pathology ; Tumor Markers, Biological/*analysis ; Tumor Suppressor Protein p53/metabolism ; Vascular Endothelial Growth Factor A/metabolism

PURPOSE: The expression of p53 in patients with rectal cancer who underwent preoperative chemoradiationand and its potential prognostic significance were evaluated. MATERIALS AND METHODS: p53 expression was examined using immunohistochemistry in pathologic specimens from 210 rectal cancer patients with preoperative chemoradiotherapy and radical surgery. All patients were classified into two groups according to the p53 expression: low p53 (<50% nuclear staining) and high p53 (> or =50%) groups. RESULTS: p53 expression was significantly associated with tumor location from the anal verge (p=0.036). In univariate analysis, p53 expression was not associated with disease-free survival (p=0.118) or local recurrence-free survival (p=0.089). Multivariate analysis showed that tumor distance from the anal verge (p=0.006), ypN category (p=0.011), and perineural invasion (p=0.048) were independent predictors of disease-free survival; tumor distance from the anal verge was the only independent predictor of local recurrence-free survival. When the p53 groups were subdivided according to ypTNM category, disease-free survival differed significantly in patients with ypN+ disease (p=0.027) only. CONCLUSION: Expression of p53 in pathologic specimens as measured by immunohistochemical methods may have a significant prognostic impact on survival in patients with ypN+ rectal cancer with preoperative chemoradiotherapy. However, it was not an independent predictor of recurrence or survival.
Adult ; Aged ; *Chemoradiotherapy ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Recurrence, Local/pathology ; Neoplasm Staging ; *Preoperative Care ; Prognosis ; Rectal Neoplasms/diagnosis/*metabolism/surgery/*therapy ; Tumor Suppressor Protein p53/analysis/immunology/*metabolism

BACKGROUND/AIMS: Maximal duration of intravenous (IV) corticosteroid (CS) treatment and efficacy of cyclosporin A (CsA) have not been clarified for patients with severe ulcerative colitis. We aimed to evaluate and compare the effectiveness of CS and CsA combination therapy with prolonged CS therapy alone in patients with severe UC refractory to initial CS therapy. METHODS: We retrospectively reviewed the medical records of 84 episodes of severe UC in 59 patients between April 1999 and May 2005. RESULTS: Among 84 episodes with IV CS therapy, 45 (53.6%) experienced an early response, while 39 (46.4%) did not respond within 2 weeks. The remaining 36 episodes excluding 3 which underwent colectomy were assigned to either combination therapy of IV CS and CsA or prolonged IV CS treatment alone for additional 2 weeks. Twelve of 16 episodes (75.0%) responded to therapy with combinations of IV CsA and CS, and 16 of 20 episodes (80.0%) to prolonged IV CS treatment alone. There was no statistical difference in response and colectomy rate after 4 weeks between CsA-use group and CsA-non-use group (p=1.00). CONCLUSIONS: These results suggest that CS and CsA combination has no additional benefit over prolonged CS therapy alone in terms of short-term response and that CS can be safely prolonged even after the first 14 days of treatment for severe UC.
Aged ; Aged, 80 and over ; Antibodies, Monoclonal ; Carcinoma, Squamous Cell/*metabolism/pathology ; Cyclin D1/immunology/*metabolism ; Cyclin-Dependent Kinase Inhibitor p16/immunology/*metabolism ; Esophageal Neoplasms/*metabolism/pathology ; Esophagus/*abnormalities/metabolism/pathology ; Female ; G1 Phase ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Tumor Markers, Biological/metabolism ; Tumor Suppressor Protein p53/immunology/*metabolism

OBJECTIVETo explore the specific cytotoxic T lymphocyte (CTL) induced by dendritic cells (DC), which were transfected by the plasmid pC53-SN3 encoding p53 gene.

METHODSDC derived from HLA-A2(+) mononuclear cells of the 24-lung cancer patients was transfected with the plasmid pC53-SN3 by lipofectamine and then co-cultured with auto-unpurified T cells to induce potent CTL (T-pC53-SN3). The cytolysis of specific CTL against Calu-6, a HLA-A2(+) human lung cancer cell line, was measured by using lactate dehydrogenase (LDH) releasing assay.

RESULTSThe expression of CD(1a) and CD(83), the correlative markers of DC, increased apparently after transfected with plasmid pC53-SN3, the expression rate was (5.45 +/- 0.89)% and (3.26 +/- 0.47)% versus (52.15 +/- 11.56)% and (25.78 +/- 12.35)%. CD(14) decreased apparently, but other DC correlative markers of CD(1a), CD(40), CD(86), and HLA-DR remained almost the same as that before transfection. Compared with T-IL-2, the CTL derived from PBMNC stimulated by IL-2 (100 U/ml), the cytolytic activity of T-pC53-SN3 against Calu-6 cell line showed a significant increase, but cytolytic activity was 56.79 +/- 15.67 and 39.33 +/- 9.88, respectively, when effect cells: target cells was 10:1. The expression of the CD(8), CD(69), and CD(45)RO/CD(8) of T-pC53-SN3 cells increased significantly, but that of CD(3), CD(4), CD(86), ect, was not significantly different from those of T-pCMV-neo.

CONCLUSIONSIt showed that DC transfected by p53 gene could induce potent HLA-A(2) restrictive CTL to kill tumor cell efficiently.

Antigens, CD ; analysis ; B7-2 Antigen ; CD40 Antigens ; analysis ; Cell Line, Tumor ; immunology ; Coculture Techniques ; Cytotoxicity, Immunologic ; immunology ; Dendritic Cells ; drug effects ; immunology ; metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor ; pharmacology ; Humans ; Interleukin-4 ; pharmacology ; Membrane Glycoproteins ; analysis ; T-Lymphocytes ; immunology ; Tumor Suppressor Protein p53 ; genetics ; physiology

BACKGROUNDp53 is a tumor suppressor and plays a key role in regulating cell hyperplasia, repairing DNA and inducing apoptosis. This study was to investigate p53 expression in fibroblast-like synoviocytes (FLS) and its effect on CD4(+) T lymphocytes from patients with active rheumatoid arthritis (RA).

METHODSHuman FLS were transfected with p53 siRNA and cocultured with CD4(+) T lymphocytes from patients with active RA. The expressions of osteoprotegerin and interleukin (IL)-6 were detected in p53 siRNA and scramble siRNA-transfected FLS. In addition, protein levels of interferon (IFN)-γ, IL-17, IL-4 and CD25 as well as mRNAs of IFN-γ, retinoic acid-related orphan receptor (ROR)-γt, IL-17 and Foxp3 in cocultured CD4(+) T lymphocytes were also measured.

RESULTSIL-6 decreased in p53-knockdown FLS while osteoprotegerin expression was not altered. FLS with p53 deletion significantly increased the production of IL-17 and IFN-γ by CD4(+) T cells and upregulated Foxp3 mRNA expression without effects on the proportion of CD4(+)CD25(high) T lymphocytes.

CONCLUSIONp53 in FLS might regulate Th1 and Th17 functions in patients with RA and participate in the pathogenesis of RA.

Arthritis, Rheumatoid ; genetics ; immunology ; metabolism ; CD4-Positive T-Lymphocytes ; metabolism ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Forkhead Transcription Factors ; genetics ; metabolism ; Humans ; Interleukin-6 ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Synovial Membrane ; cytology ; Tumor Suppressor Protein p53 ; genetics ; metabolism