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1.
Hum Pathol ; 113: 20-27, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33887301

RESUMO

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Resistencia a Medicamentos Antineoplásicos , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Ovarianas/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Paclitaxel/uso terapêutico , Valor Preditivo dos Testes , Fatores de Tempo
2.
Int Immunopharmacol ; 90: 107144, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33187907

RESUMO

Metastasis commonly occurs in colorectal cancer (CRC) patients and confers a poor prognosis. B7-H4, an immune checkpoint molecule, has been found to be expressed in numerous tumor tissues and play critical roles in tumor progression. However, B7-H4 expression and its prognostic significance in different metastases from CRC remain unclear. In the present study, we screened a novel mouse anti-human B7-H4 monoclonal antibody (mAb) which exhibited a higher degree of recognition and sensitivity than the commercial reagent in immunohistochemistry (IHC). Using this antibody, overall 110 metastatic and paired primary lesions of CRC were analyzed for their expression of B7-H4, CD8 and CD68. Our results showed that expression of B7-H4 and CD68 in metastastic lesions was significantly higher than that in matched primary lesions (P = 0.0016, P < 0.0001). We also found a significant increase of CD68-positive immune cell infiltration in the B7-H4 high expressing metastases (P = 0.041). Moreover, upregulated B7-H4 in metastatic lesions was correlated with poor prognosis of patients (P = 0.014), while in primary lesions, B7-H4 combined with CD8 was associated with the overall survival (OS) (P = 0.043). Further, B7-H4 expression in metastatic lesions was significantly correlated with hazard ratio (HR) both in univariate and multivariate analysis. Altogether, B7-H4 in metastatic lesions is promising to be a potential prognostic indicator of CRC, and may promote tumor progression and metastasis of this cancer.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Idoso , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígenos CD8/análise , Células CHO , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Cricetulus , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Microambiente Tumoral , Regulação para Cima
3.
Ann Palliat Med ; 9(4): 1953-1957, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32692215

RESUMO

BACKGROUND: B7-H4, a member of the B7 family, is detected in various cancers and is closely related to tumor development and prognosis. However, little is known about the clinical value of B7-H4 in small cell lung cancer (SCLC). METHODS: Immunohistochemical analysis was carried out on 103 SCLC specimens. The relationship between B7-H4 staining and the major clinical parameters of SCLC was analyzed, and the two-year survival rates were investigated by chi-square test. RESULTS: Only 5.83% of the SCLC specimens tested positive for B7-H4. B7-H4 was detected on the membrane and in the cytoplasm of tumor cells. In contrast, B7-H4 expression was not detected in normal lung tissue samples. B7-H4 was not found to be associated with major clinical parameters, such as tumor size, gender, age, smoking status, limited/extensive stage, tumor node metastasis, Karnofsky Performance Status, lymph node metastasis status, distant metastasis, or ki-67. Moreover, no obvious differences were observed in the two-year survival rates of B7-H4 positive or B7-H4-negative SCLC patients. CONCLUSIONS: There is no correlation between B7-H4 expression and the proliferation or progression of SCLC. Therefore, B7-H4 is not a useful biomarker for SCLC prognosis.


Assuntos
Biomarcadores , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Inibidor 1 da Ativação de Células T com Domínio V-Set , Biomarcadores/análise , Humanos , Metástase Linfática , Prognóstico , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise
4.
J Thorac Cardiovasc Surg ; 158(3): 911-919.e6, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235357

RESUMO

OBJECTIVES: Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non-small cell lung cancer. METHODS: Specimens of patients undergoing resection of stage I to III non-small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset. RESULTS: A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P < .001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P = .013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P < .001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival. CONCLUSIONS: Increased Ki67 expression is associated with biologically aggressive non-small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/imunologia , Proliferação de Células , Neoplasias Pulmonares/imunologia , Idoso , Antígenos CD/análise , Antígenos B7/análise , Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Diferenciação Celular , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Proteína Coestimuladora de Linfócitos T Induzíveis/análise , Antígeno Ki-67/análise , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Microambiente Tumoral , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Proteína do Gene 3 de Ativação de Linfócitos
5.
Zhonghua Zhong Liu Za Zhi ; 39(7): 524-527, 2017 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-28728299

RESUMO

Objective: To evaluate the value of combined detection of negative costimulatory molecule B7-H4 and carcinoembryonic antigen (CEA) in diagnosing malignant and benign pleural effusion. Methods: Ninety-seven pleural effusion specimen were collected, 55 of which were diagnosed as malignant pleural effusion and 42 were benign pleural effusion. Enzyme-linked immunosorbent assay(ELISA) was used to examine the concentration of B7-H4 and CEA in pleural effusion. Electro-chemiluminescence immunoassay was used to detect the CEA level in pleural effusion. Receiver operating characteristic (ROC) curve was established to analyze and evaluate the single or combined detection of B7-H4 and CEA in diagnosing malignant and benign pleural effusion. Results: The concentrations of B7-H4 and CEA in malignant pleural effusion (MPE) group were (60.08±35.04) ng/ml and (41.49±37.16) ng/ml, respectively, obviously higher than (27.26±9.55) ng/ml and (2.41±0.94) ng/ml of benign pleural effusion (BPE) group (both P<0.01). Area under curve (AUC) of B7-H4 was 0.884 in MPE groupand the diagnostic sensitivity and specificity were 81.8% and 90.5%, respectively, at the optimized cut off value of 37.25 ng/ml. Likewise, area under curve (AUC) of CEA was 0.954 and the sensitivity and specificity were 87.3% and 95.2%, respectively, at the cut off value of 4.18 ng/ml. When B7-H4 >37.25 ng/ml or CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 90.9% and the specificity was elevated to 88.1%. When B7-H4 >37.25 ng/ml and CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 78.2% and the specificity was elevated to 97.6%. The sensitivity and specificity of combined detection of B7-H4 and CEA to diagnose MPE were elevated to 90.9% and 97.6%, respectively. The level of B7-H4 in MPE and BPE were both positively correlated with CEA (r=0.670, P=0.001 in MPE and r=0.002, P=0.001 in BEP). Conclusions: B7-H4 is a potential tumor marker in diagnosing the benign and malignant pleural effusion. Although the diagnostic value of B7-H4 may not precede to CEA, the combined detection of B7-H4 and CEA can improve the diagnostic sensitivity and specificity of MPE.


Assuntos
Biomarcadores Tumorais/análise , Antígeno Carcinoembrionário/análise , Derrame Pleural Maligno/diagnóstico , Derrame Pleural/diagnóstico , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Área Sob a Curva , Diagnóstico Diferencial , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Humanos , Derrame Pleural Maligno/química , Curva ROC , Sensibilidade e Especificidade , Fatores de Transcrição
6.
Hum Pathol ; 66: 79-85, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28600225

RESUMO

B7-H4 belongs to the immune costimulatory B7 family and is thought to negatively regulate T-cell-mediated immunity, and may contribute an important role in tumor immune evasion. Although the expression of B7-H4 has been observed in human pancreatic cancer, the prognostic significance of this expression is poorly understood. This present study explored the prognostic value of B7-H4 in pancreatic cancer. Patients with pancreatic cancer and healthy controls were recruited at the Second Affiliated Hospital to Zhejiang University from January 2011 to December 2014. Expression of B7-H4 was assessed by immunohistochemistry. Immunohistochemical analysis indicated that B7-H4 was expressed in 100% (188/188) of the pancreatic cancer tumor tissue samples, while only in 68% (17/25) of normal pancreatic tissue samples. Furthermore, the expression levels of B7-H4 in pancreatic cancer patients were significantly higher than in controls (P<.01). A significant difference in B7-H4 expression was observed between patients with late tumor-node-metastasis (TNM) stage (III and IV) and early TNM stage (I and II) (P<.01). The expression of B7-H4 was associated with distant metastasis (P<.01) and differentiation (P<.01). In addition, B7-H4 expression (P<.01), distant metastasis (P<.01), TNM stage (P<.01), differentiation (P<.01) and chemotherapy treatment (P<.05) were indicators of poor overall survival time. Multivariate survival analysis indicated that B7-H4 expression, distant metastasis, and chemotherapy treatment (P<.05) were independent prognostic indicators of poor overall survival. In conclusion, B7-H4 is highly expressed in pancreatic cancer, and is an independent predictor of poor prognosis in patients with pancreatic cancer. B7-H4 may represent an immunotherapeutic target in pancreatic cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/imunologia , Neoplasias Pancreáticas/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/terapia , Estudos de Casos e Controles , China , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Razão de Chances , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
7.
Hum Pathol ; 57: 1-6, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27349304

RESUMO

The B7 family of immune costimulatory ligands is a group of cell surface proteins that bind to the surface receptors of lymphocytes to fine-tune immune responses. The aberrant expression of these proteins plays a key role in tumor immune evasion. Immunotherapy targeting certain B7 family members, including programmed death ligand 1, has proven quite effective in suppressing tumor growth. However, why such therapy works in only a subgroup of tumors is unclear. We hypothesized that other B7 family members, either alone or in concert with programmed death ligand 1, play a crucial role in tumor pathogenesis and progression. We therefore examined the expression of a newly discovered B7 family member, B7-H4, in 306 cases of ovarian serous carcinoma by immunohistochemistry. We found that 91% (267/293) of the high-grade ovarian serous carcinomas and 69% (9/13) of the low-grade ovarian serous carcinomas expressed B7-H4. The difference between B7-H4 expression in high-grade and low-grade ovarian serous carcinoma was statistically significant (P=.002). Moreover, B7-H4 protein expression in high-grade serous carcinoma was associated with tumor stage (P<.01) but not overall survival or disease-free survival. In conclusion, B7-H4 is frequently expressed in ovarian serous carcinomas, especially high-grade serous carcinomas, and may represent a novel immunotherapeutic target in this cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/imunologia , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/terapia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
Clin Exp Med ; 16(3): 351-6, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25924930

RESUMO

Pancreatic cancer (PC) is a leading cause of cancer death worldwide, especially in Western societies. Its aggressive nature and poor prognosis increase the need for identifying new and more accurate diagnostic and prognostic tools. We studied 41 patients who had undergone radical surgical resection for PC, investigated B7H4 protein expression in the PC tissue specimens of these patients by immunohistochemistry and analyzed several clinical and pathological features. The positive expression of the B7H4 antigen was associated with a negative impact of chemotherapy with gemcitabine on patient survival and also correlated with high CA19.9 serum levels and poorly differentiated tumors. Moreover, patients that overexpressed B7H4 antigen had worse prognosis compared to the ones that did not overexpress B7H4. B7H4 antigen is a negative prognostic marker for PC patients and also seems to express resistance of PC patients to chemotherapy with gemcitabine.


Assuntos
Adenocarcinoma/patologia , Antígenos Glicosídicos Associados a Tumores/análise , Biomarcadores Tumorais/análise , Neoplasias Pancreáticas/patologia , Soro/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Gencitabina
9.
Tumour Biol ; 37(3): 2961-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26411671

RESUMO

The coinhibitory molecules, B7-H3 and B7-H4, have shown negative regulation in T cell activation and tumor-associated macrophage (TAM) polarization in tumor-specific immunity. Here, we investigated the expression of B7-H3 and B7-H4 in human and murine esophageal squamous cell carcinoma (ESCC) tissues to define their clinical significance and mechanism in a tumor microenvironment. In the present study, B7-H3 and B7-H4 were expressed in 90.6 and 92.7 % samples, respectively. High B7-H3 and B7-H4 expression was associated with advanced TNM stage and lymph node metastasis (p < 0.05, respectively). Patients with both B7-H3 and B7-H4 high-expressed tumors had the poorest prognosis (26.7 months), whereas those with both low-expressed tumors had the best survival (56.7 months). B7-H3 and B7-H4 expression were inclined to be positively related to the infiltration intensity of Treg cells and TAMs (p < 0.05, respectively), and B7-H3 expression is negatively associated with the intensity of CD8(+) T cells (p < 0.05). In 4-nitroquinoline 1-oxide (4-NQO)-induced murine models, high B7-H3 expression could only be detected at carcinoma stage, but abnormal B7-H4 expression appeared a little earlier at dysplasia stage. In vitro studies revealed that knockdown of B7-H3 on tumor cells suppressed ESCC cell migration and invasion, while knockdown of B7-H4 could inhibit ESCC cell growth. Overall, B7-H3 and B7-H4 are involved in ESCC progression and development and their coexpression could be valuable prognostic indicators. Interference of these negative regulatory molecules might be a new strategy for treating ESCC.


Assuntos
Antígenos B7/fisiologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/fisiologia , 4-Nitroquinolina-1-Óxido/toxicidade , Adulto , Idoso , Animais , Antígenos B7/análise , Carcinoma de Células Escamosas/induzido quimicamente , Linhagem Celular Tumoral , Neoplasias Esofágicas/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Linfócitos do Interstício Tumoral/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Quinolonas/toxicidade , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise
10.
Biomarkers ; 20(4): 271-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26301886

RESUMO

OBJECTIVE: To evaluate the diagnostic value of sB7-H4 and CEA in both serum and pleural effusion of lung cancer patients. METHODS: Levels of sB7-H4 and CEA in 90 patients with malignant pleural effusion due to lung cancer and 58 patients with benign pleural effusion were measured by ELISA. RESULTS: The sB7-H4 and CEA levels in pleural effusion, serum and their ratio (F/S) were higher in lung cancer group than that in benign group (p < 0.01). The diagnostic efficiency of sB7-H4 combined CEA was superior to either sB7-H4 or CEA. CONCLUSIONS: Measurement of sB7-H4 and CEA might be useful diagnostic value for malignant effusion.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Pulmonares/metabolismo , Derrame Pleural Maligno/metabolismo , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adulto , Idoso , Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/análise , Antígeno Carcinoembrionário/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Derrame Pleural/sangue , Derrame Pleural/diagnóstico , Derrame Pleural/metabolismo , Derrame Pleural Maligno/sangue , Derrame Pleural Maligno/diagnóstico , Sensibilidade e Especificidade , Solubilidade , Inibidor 1 da Ativação de Células T com Domínio V-Set/sangue
11.
Int J Clin Oncol ; 20(2): 273-81, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24804867

RESUMO

OBJECTIVE: Immune escape plays an important role in tumor progression. In the present study, the expression of B7-H1, B7-H4 and Foxp3 involved in immune escape in gastric carcinoma was investigated and the corresponding clinical significance was evaluated. METHODS: Immunohistochemistry was used to detect the expression of B7-H1, B7-H4 and Foxp3 in 100 gastric cancer specimens, and 30 paracarcinoma tissues were used as the control. RESULTS: Both B7-H1 and B7-H4 showed high expression levels in gastric cancer tissues (65.0 and 71.0 %, respectively), and the expressions of B7-H1 and B7-H4 were positively correlated with the depth of tumor invasion, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage (P < 0.05). The number of Foxp3(+) Tregs was much higher in gastric cancer tissues than control tissues, which was positively correlated with lymph node metastasis (P < 0.05). Similarly, a positive correlation between B7-H1 or B7-H4 expression and the number of Foxp3(+) Tregs was observed. The median overall survival rate of patients with high expression of B7-H1, B7-H4 and Foxp3 was significantly poorer than that of patients with low expression of these proteins (P < 0.05). Cox regression multivariate analysis confirmed that lymph node metastasis, AJCC stage, and B7-H1 and Foxp3 overexpression were independent prognostic factors. CONCLUSION: B7-H1, B7-H4 and Foxp3 were overexpressed in gastric cancer tissues. B7-H1 and Foxp3 are negative prognostic factors for patients with gastric cancer.


Assuntos
Antígeno B7-H1/análise , Carcinoma/química , Neoplasias Gástricas/química , Linfócitos T Reguladores/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Carcinoma/secundário , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estômago/química , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Evasão Tumoral
12.
Int J Clin Exp Pathol ; 7(10): 6768-75, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25400757

RESUMO

OBJECTIVE: To investigate the mRNA and protein levels of B7-H4, a B7 family molecule, in human urothelial cell carcinoma (UCC), to analyze the relationship between B7-H4 protein expression level and pathological stage of UCC, and to examine the potential of B7-H4 as a prognostic factor in UCC. METHODS: mRNA and protein levels of B7-H4 were measured in pairs of tumor tissues and matched adjacent nontumor tissue obtained from patients with UCC by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining, respectively. Association of the protein level of B7-H4 with pathological tumor stage and the overall survival of UCC patients were also analyzed. RESULTS: B7-H4 mRNA and protein level were significantly higher in UCC tumor tissues compared with adjacent nontumor tissues as assessed by qRT-PCR and immunohistochemical staining, respectively. Higher B7-H4 protein levels were observed in patients with more advanced pathological stage of UCC and were also associated with decreased overall survival of patients with UCC. CONCLUSIONS: The findings from this study indicate that B7-H4 has the potential to be an independent prognostic indicator for UCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/química , Neoplasias da Bexiga Urinária/química , Urotélio/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/cirurgia , Estudos de Casos e Controles , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Urotélio/cirurgia , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética
13.
Pancreatology ; 13(6): 564-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24280570

RESUMO

OBJECTIVES: Pancreatic cancer (PC) is one of the most lethal tumors of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and chemotherapy would be a great clinical tool. A large number of potential markers have been identified lately in pancreatic cancer and their clinical utilities as prognostic tools are under investigation. METHODS: We recruited 41 patients who had undergone radical surgical resection for PC between 2003 and 2010. To investigate the prognostic factors, we evaluated 3 possible markers: B7H4, HSP27 and DJ-1 protein expressions in the tissue specimens of these 41 patients by immunohistochemistry and analyzed the clinical and pathological features of these specimens. RESULTS: The expression of the three antigens was independently associated with a negative impact of chemotherapy with gemcitabine on patient's survival. Moreover, patients who overexpressed B7H4 had worse prognosis than the ones who did not. CONCLUSIONS: B7H4, DJ-1 and HSP27 may be used in the future as prognostic markers that express resistance of pancreatic cancer patients to chemotherapy with gemcitabine.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/análise , Proteínas de Choque Térmico HSP27/análise , Peptídeos e Proteínas de Sinalização Intracelular/análise , Proteínas Oncogênicas/análise , Neoplasias Pancreáticas/diagnóstico , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Proteína Desglicase DJ-1 , Análise de Sobrevida , Gencitabina
14.
Zhonghua Yi Xue Za Zhi ; 92(2): 117-8, 2012 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-22490695

RESUMO

OBJECTIVE: To explore the diagnostic value of soluble B7-H4 (sB7-H4) in tuberculous pleural effusion and malignant pleural effusion. METHODS: A total of 98 patients of pleural effusion treated in Nanjing Chest Hospital from January 2007 to December 2009 were enrolled. The etiologies were tuberculous (n = 48) and malignant (n = 50). The levels of sB7-H4 in pleural effusion were detected by sandwich enzyme linked immunosorbent assay. The rational clinical diagnostic value was established by receiver operating characteristic (ROC) curves. RESULTS: The level of sB7-H4 in malignant pleural effusion was significant higher than that in tuberculous effusion ((65.7 ± 5.8) vs (28.6 ± 8.7) µg/L, P < 0.05). The cut-off value of sB7-H4 was 36.5 µg/L for malignant pleural effusion. And the rates of sensitivity, specificity and accuracy were 92.0%, 83.3% and 87.8% respectively. CONCLUSION: The level of sB7-H4 may be used as a valuable parameter in the differentiation of tuberculous from malignant effusion.


Assuntos
Derrame Pleural Maligno/diagnóstico , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Adulto , Idoso , Diagnóstico Diferencial , Exsudatos e Transudatos/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , Tuberculose Pleural/diagnóstico
15.
Inflammation ; 34(6): 688-97, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21120594

RESUMO

The expression and function of B7-H4, a recently identified co-inhibitory molecule of the B7 superfamily, in the pathogenesis of primary biliary cirrhosis (PBC) is still unclear. Here the expression of B7-H4 in sections from PBC patients (n = 16) was examined by immunohistochemistry and it was detected in primary bile duct epithelial cells (BECs) which were isolated from PBC patients by flow cytometry (FACs). Moreover, we also analyzed BECs-associated B7-H4 function through knock-down of its expression via RNA interference (RNAi) in vitro. Immunohistochemistry and FACs evidenced that the expression of B7-H4 was restricted in the cytoplasm of BECs from PBC patients, while it was completely absent in normal liver tissues. The cytoplasmic B7-H4 gene was cloned, and sequenced analysis showed it was encoded by the same gene to the membrane B7-H4. Interesting, silencing B7-H4 by specific RNAi resulted in enhanced FasL expression and BEC apoptosis. Conversely, interruption of Fas\FasL interaction with using FasL blocking antibodies (clone 4H9) reversed cell apoptosis. Our results suggested that the intracellular B7-H4 appears to prevent Fas/FasL-mediated BEC apoptosis during the progression of PBC, and indicates B7-H4 is a possible target for therapeutic intervention of this disease.


Assuntos
Apoptose , Ductos Biliares/patologia , Células Epiteliais/patologia , Cirrose Hepática Biliar/patologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/fisiologia , Proteína Ligante Fas , Humanos , Análise de Sequência de DNA , Distribuição Tecidual , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética , Receptor fas
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