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1.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
2.
Zhonghua Bing Li Xue Za Zhi ; 49(11): 1114-1119, 2020 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-33152814

RESUMO

Objective: To study the clinicopathological features and PD-L1 expression of microsatellite instability-high (MSI-H) gastric cancer. Methods: The clinicopathological data of the 2 472 patients who had undergone radical surgical resection and been performed immunohistochemical staining of four major mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) from March 2014 to December 2018 at Peking University Cancer Hospital were collected. One hundred and seventy-one patients showed mismatch repair-deficient (dMMR), and microsatellite instability of these patients were detected with polymerase chain reaction (PCR). Then, taken PCR results as the standard, PD-L1 was assessed using immunohistochemistry (IHC) in the MSI-H gastric cancers. Results: MSI-H (vs. MSI-L) in gastric cancers was associated with female gender, advanced age, gastric-antrum location, intestinal type, lesion diameter exceeding 5 cm, absence of lymph node metastasis and positive PD-L1 expression (P<0.05, respectively). Combined positive score (CPS) was an independent risk factor (P=0.026, HR=8.385, 95%CI=1.293-54.367). Although no relationship between PD-L1 expression pattern and prognosis was observed,"diffuse-pattern" of the PD-L1 expression was related to lymphatic-vascular invasion (P=0.007) and infiltration depth (P=0.04). Among the patients with MSI-H and PD-L1 positive gastric cancer, the patients who experienced recurrence or died all had the pattern of "diffuse" PD-L1 expression. Also, regarding the expression level and staining pattern of PD-L1, the metastasis lesion of lymph node had a high coincidence with primary site (P=0.45). Conclusions: MSI-H gastric cancer shows distinctive clinicopathological characteristics. The CPS can be used as a prognostic indicator in MSI-H gastric cancers, while the "diffuse-pattern" of PD-L1 expression could possibly be used as a prognostic indicator. The patients with advanced gastric cancer could obtain the expression level and staining pattern of PD-L1 using the biopsy material of metastatic lesions.


Assuntos
Neoplasias Gástricas , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Instabilidade de Microssatélites , Prognóstico , Neoplasias Gástricas/genética
3.
Nat Commun ; 11(1): 5415, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110069

RESUMO

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.


Assuntos
Anticorpos/administração & dosagem , Células Dendríticas/imunologia , Neoplasias/tratamento farmacológico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Resistência a Medicamentos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
4.
Cells ; 9(10)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003471

RESUMO

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Células Dendríticas/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Pneumonia Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Cultivadas , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia
5.
Zhonghua Yi Xue Za Zhi ; 100(34): 2682-2688, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-32921017

RESUMO

Objective: The aim of present study was to investigate the influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Methods: This study was designed as a retrospective analysis, and a total of 278 patients with postoperative NSCLC who received platinum-based adjuvant chemotherapy from January 2012 to December 2018 in the Department of Respiratory Medicine of the First affiliated Hospital of Zhengzhou University were included in this study. Biological specimens of the patients were collected during hospitalization. Recurrence status and adverse reactions were evaluated in the hospital during adjuvant chemotherapy. Survival data of the patients were obtained through telephone follow-up after completing the fixed cycle of adjuvant chemotherapy. DNA extracted from the collected hematological specimens was genotyped for PD-L1 gene polymorphism. Additionally, postoperative cancer tissue specimens from 68 patients were collected for RNA extraction in order to perform the PD-L1 mRNA expression analysis. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis. Results: Prognostic results indicated that the median disease-free survival (DFS) of the 278 patients with NSCLC was 3.2 years and the median overall survival (OS) was 4.9 years. The prevalence of -1813G>C polymorphism were: GG genotype 173 cases (62.23%), GC genotype 92 cases (33.09%), CC genotype 13 cases (4.68%), the minor allele frequency was 0.21, the distribution of the three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.864). In view of the rare frequency of CC genotype, GC and CC genotype were merged in the following analysis. The survival analysis results of the two genotype groups suggested that the median DFS of patients with GG and GC/CC genotype was 2.7 and 4.0 years, which was statistically significant (P=0.013). Furthermore, the median OS of patients with GG and GC/CC was 4.0 and 5.4 years respectively, which was statistically significant as well (P=0.009). However, the safety analysis failed to find the significant association between the polymorphism and adverse events (P>0.05). Interestingly, expression analysis of RNA extracted from cancer tissues specimens indicated that the PD-L1 mRNA expression of the patients with GG genotype were significantly higher than those of the GC/CC genotype (3.67±0.65 vs 2.69±0.78, P<0.001). Conclusion: The prognosis of patients with postoperative non-small cell lung cancer who received platinum-based adjuvant chemotherapy is influenced by -1813G>C polymorphism of PD-L1 gene.


Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Quimioterapia Adjuvante , Humanos , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Platina/uso terapêutico , Prognóstico , Estudos Retrospectivos
6.
Lancet Oncol ; 21(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888453

RESUMO

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(4): 418-425, 2020 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879067

RESUMO

The clinical application of immune checkpoint inhibitors (ICIs) lead to dramatic changes in the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC), but the efficacy of ICIs in oncogene-driven NSCLC is controversial. Existing research shows that the efficacy of ICIs may be related to different types of driver genes, programmed cell death-ligand 1 (PD-L1) level, and tumor mutational burden (TMB). It may involved in other factors, such as clinical characteristics, and immune cell density. ICIs monotherapy or combination therapy may play a role in a subset of oncogene-driven NSCLC patients, but further studies are needed to select these patients, which may be an important direction for the future development of advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno B7-H1/genética , Biomarcadores Tumorais , Humanos , Imunoterapia
9.
Nat Commun ; 11(1): 4835, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973173

RESUMO

Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.


Assuntos
Antígeno B7-H1/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Linfocitária , Animais , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Regulação para Cima
10.
Life Sci ; 259: 118239, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784058

RESUMO

AIMS: MicroRNAs (miRs) are key modulators of cellular processes such as proliferation, apoptosis, as well as anti-cancer immune responses. Here, we evaluated the role of miR-424-5p in breast cancer (BC) and investigated its effects on T cell-related immune response. MAIN METHODS: BC tissues and cell lines were prepared and the expression of miR-424-5p and PD-L1, as well as the underlying molecular pathways, were assessed via qRT-PCR and western blotting. The MTT assay and flow cytometry were used to assess the effect of miR-424-5p on proliferation, apoptosis, autophagy, and cell cycle progression. The co-culture of T cells with MDA-MB-231 was performed for evaluating the role of miR-424-5p in rescuing T cell exhaustion. KEY FINDINGS: The results indicated the down-regulation of miR-424-5p and up-regulation of PD-L1 expression in BC tissue specimens. MiR-424-5p transfection into PD-L1 overexpressing MDA-MB-231 cells decreased the expression of PD-L1. Also, miR-424-5p could reduce MDA-MB-231 cell viability through modulating apoptosis and autophagy pathways. Furthermore, miR-424-5p transfection leads to decreased colony formation and increased cell number at the G2/M phase. Western blot analysis illustrated that miR-424-5p could exert its anti-proliferative effect via modulating PTEN/PI3K/AKT/mTOR pathway. Moreover, it was demonstrated that suppression of PD-L1 by miR-424-5p could participate in regulating the expression of effector cytokines in T cells. SIGNIFICANCE: MiR-424-5p could be considered as a potential tumor-suppressor miR in regulating BC cellular growth, apoptosis, and T cell-related immune response through targeting PD-L1, and its downstream mediators. Therefore, we recognized miR-424-5p as a promising candidate for miR restoration therapy in BC patients.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Idoso , Apoptose/fisiologia , Autofagia/fisiologia , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
11.
Lancet Oncol ; 21(9): 1155-1164, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32771088

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto Jovem
13.
Zhonghua Fu Chan Ke Za Zhi ; 55(8): 529-534, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32854477

RESUMO

Objective: To examine the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in epithelial ovarian cancer (EOC) tissues, and investigate the correlation among their expression, clinicopathological features and prognosis. Methods: The specimens of 180 patients with EOC treated in the First Affiliated Hospital of Dalian Medical University from October 2002 to December 2013 were confirmed by pathological examination. The pathological tissue specimens of subtypes ,included 120 cases of serous carcinoma, 30 cases of mucinous carcinoma, 20 cases of endometrioid carcinoma, and 20 cases of clear cell carcinoma. The normal paracancerous tissues of 50 cases randomly selected from the 180 patients as control group. Immunohistochemical SP method was used to detect the expressions of both PD-1 and PD-L1 in epithelial ovarian cancer tissues, and the relationships among their expressions,the clinicopathological parameters and prognosis were respectively analyzed. Results: (1) PD-1 was expressed in lymphocytes infiltrated in EOC tissues, and PD-L1 was expressed in the cell membranes of cancer tissues. In all EOC cases, 33 cases (18.3%, 33/180) of both PD-1 and PD-L1 were highly expressed, and only 1 (2.0%, 1/50) of control group showed high expression. There was statistically significant difference between two groups (P<0.01). (2) Among the four subtypes tissue specimens of EOC, the high expression rate of PD-1 was 25.0% (30/120) for serous carcinoma, 3/15 for endometrioid carcinoma, 0 (0/30) for mucinous carcinoma, and 0 (0/15) for clear cell carcinoma. The high expression rate of PD-L1 was 23.3% (28/120) for serous carcinoma, 3.3% (1/30) for mucinous carcinoma, 2/15 for endometrioid carcinoma, and 2/15 for clear cell carcinoma. Both PD-1 and PD-L1 expressions in the four sub-types of tissue specimens were significantly different (P<0.05). The high expression rate of both PD-1 and PD-L1 was 9.2% (8/87) in the early stage and 26.9% (25/93) in the late stage. There was a statistically significant difference between the two groups (P<0.01). Similarly, the expression of both PD-1 and PD-L1 were significantly higher in the cases of high-grade EOC (type Ⅱ) than those of low-grade (type Ⅰ) and in the cases of EOC distributed bilaterally than that distributed unilaterally, and there were statistically significant differences (P<0.05). (3) The Kaplan-Meier survival analysis showed that the survival time were respectively 35 and 36 months in the cases with high expressions of both PD-1 and PD-L1, and the survival time were the same as 61 months in the cases with low expression of both PD-1 and PD-L1, and the comparison was statistically significant (P<0.05). Conclusions: The expression levels of PD-1 and PD-L1 in EOC tissues are higher than those in adjacent tissues, especially in serous carcinomas. The expression of both PD-1 and PD-L1 is higher in specimens of the patients with advanced stages. The results showed that the high expression of both PD-1 and PD-L1 is an indicator of poor prognosis of patients suffering from EOC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1 , RNA Mensageiro/genética
14.
Surgery ; 168(4): 610-616, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32631655

RESUMO

BACKGROUND: Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab. METHODS: In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity. RESULTS: Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8). CONCLUSION: Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.


Assuntos
Adenocarcinoma/terapia , Antineoplásicos Imunológicos/uso terapêutico , Eletroporação/métodos , Nivolumabe/uso terapêutico , Neoplasias Pancreáticas/terapia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adulto , Idoso , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Expressão Gênica , Humanos , Interferon gama/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/genética , Subpopulações de Linfócitos T
15.
PLoS One ; 15(7): e0235518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614928

RESUMO

Interruption of the programmed death 1 (PD-1) / programmed death ligand 1 (PD-L1) pathway is an established and effective therapeutic strategy in human oncology and holds promise for veterinary oncology. We report the generation and characterization of monoclonal antibodies specific for canine PD-1 and PD-L1. Antibodies were initially assessed for their capacity to block the binding of recombinant canine PD-1 to recombinant canine PD-L1 and then ranked based on efficiency of binding as judged by flow cytometry. Selected antibodies were capable of detecting PD-1 and PD-L1 on canine tissues by flow cytometry and Western blot. Anti-PD-L1 worked for immunocytochemistry and anti-PD-1 worked for immunohistochemistry on formalin-fixed paraffin embedded canine tissues, suggesting the usage of this antibody with archived tissues. Additionally, anti-PD-L1 (JC071) revealed significantly increased PD-L1 expression on canine monocytes after stimulation with peptidoglycan or lipopolysaccharide. Together, these antibodies display specificity for the natural canine ligand using a variety of potential diagnostic applications. Importantly, multiple PD-L1-specific antibodies amplified IFN-γ production in a canine peripheral blood mononuclear cells (PBMC) concanavlin A (Con A) stimulation assay, demonstrating functional activity.


Assuntos
Anticorpos Monoclonais/imunologia , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Cães , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Peptidoglicano/farmacologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo
16.
Anticancer Res ; 40(7): 3733-3742, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620612

RESUMO

BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1/CD274) elicits T-cell anergy, leading to immune suppression. We aimed to determine the prognostic relevance of PD-L1 expression in the blood of breast cancer (BC) patients. MATERIALS AND METHODS: We measured PD-L1 mRNA expression in blood and tumor tissues of BC patients using RT-qPCR and a dataset from The Cancer Genome Atlas, and performed a survival analysis of PD-L1 expression in the blood of 330 BC patients. Flow cytometric analysis was performed using blood cells. RESULTS: No statistical difference in PD-L1 expression was seen between normal controls and BC in blood or tissues. There was a significant positive correlation between the PD-L1 expression levels in blood and tissues. Decreased PD-L1 expression in blood or tissues was associated with poor recurrence-free survival. PD-L1 is mainly expressed in polymorphonuclear leukocytes. CONCLUSION: Low expression of PD-L1 in the blood could serve as a biomarker of poor prognosis in BC patients.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , RNA Mensageiro/genética , Idoso , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/patologia , Prognóstico
17.
PLoS One ; 15(7): e0228302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628668

RESUMO

Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.


Assuntos
Antígeno B7-H1/metabolismo , Vírus da Hepatite B/imunologia , Interferon-alfa/farmacologia , Interferon gama/farmacologia , Fator de Transcrição STAT1/metabolismo , Linfócitos T/imunologia , Regulação para Cima/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/química , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Sítios de Ligação , Linhagem Celular , Hepatite B/tratamento farmacológico , Hepatite B/veterinária , Antígenos de Superfície da Hepatite B/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição STAT1/química , Linfócitos T/metabolismo
18.
Arch Biochem Biophys ; 690: 108479, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679194

RESUMO

The upregulation of checkpoint inhibitor PD-L1 expression has recently been associated with nasopharyngeal carcinoma (NPC) resistance to therapy. The mechanism of induction of PD-L1 has also been linked to enhanced aerobic glycolysis promoted by HIF1-α dysregulation and LDH-A activity in cancer. Here, we investigated the effect of the anti-tumoral compound Silibinin on HIF-1α/LDH-A mediated cancer cell metabolism and PD-L1 expression in NPC. Our results demonstrate that exposure to Silibinin potently inhibits tumor growth and promotes a shift from aerobic glycolysis toward oxidative phosphorylation. The EBV + NPC cell line C666-1 and glycolytic human tumor explants treated with Silibinin displayed a reduction in LDH-A activity which consistently associated with a reduction in lactate levels. This effect was accompanied by an increase in intracellular citrate levels in C666-1 cells. Accordingly, expression of HIF-1α, a critical regulator of glycolysis, was down-regulated after treatment. This event associated with a down-regulation in PD-L1. Altogether, our results provide evidence that silibinin can alter PD-L1 expression by interfering with HIF-1α/LDH-A mediated cell metabolism in NPC. These results provide a new perspective for Silibinin use to overcome PD-L1 mediated NPC resistance to therapy.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Antígeno B7-H1/genética , Glicólise/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Silibina/metabolismo , Adolescente , Adulto , Antineoplásicos Fitogênicos/farmacologia , Antígeno B7-H1/metabolismo , Biópsia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico , Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactato Desidrogenase 5/metabolismo , Pessoa de Meia-Idade , Fosforilação Oxidativa , Transdução de Sinais , Silibina/farmacologia
19.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32612152

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia Viral/imunologia , Pneumonia/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/genética , Apirase/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
20.
PLoS One ; 15(7): e0235705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649682

RESUMO

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.


Assuntos
Antineoplásicos/farmacologia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Linfócitos T/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Interferons/farmacologia , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo
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