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1.
Recent Results Cancer Res ; 214: 169-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473853

RESUMO

Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8+ T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8+ T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.


Assuntos
Linfócitos T CD8-Positivos/citologia , Imunoterapia , Melanoma/terapia , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais , Antígeno B7-H1 , Europa (Continente) , Humanos , Microambiente Tumoral
2.
Medicine (Baltimore) ; 98(38): e17257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567999

RESUMO

Recent availability of immune checkpoint inhibitors has facilitated research involving programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1). However, the incidence and clinical implication of PD-1 and PD-L1 expression in prostate cancer remain poorly understood. The current study aimed to determine the status of PD-1/PD-L1 expression in prostate cancer specimens and its prognostic significance.We immunohistochemically stained for PD-1 and PD-L1 in our tissue microarray (TMA) consisting of radical prostatectomy specimens. The expression of PD-1/PD-L1 was designated as positive when moderate to strong staining or weak staining was seen in at least 1% or 10%, respectively, of tumor cells and/or associated immune cells. We then evaluated the relationship between the expression of each protein and clinicopathological features available for our patient cohort.PD-1 and PD-L1 were positive in 3 (1.5%) and 1 (0.5%) of 201 non-neoplastic prostate tissues, and also in 17 (7.7%) and 29 (13.2%) of 220 prostate cancers, respectively. PD-1 and PD-L1 were also expressed in tumor-infiltrating lymphocytes/macrophages in 172 (78.2%) and 33 (15.0%) cases, respectively. PD-L1 expression in tumor cells was more often seen in high pT stage (pT2: 10.8% vs pT3/4: 20.4%; P = .072; pT2/3a: 11.4% vs pT3b/4: 31.6%; P = .013) or lymph node-positive (pN0: 10.1% vs pN1: 27.3%; P = .086) cases, whereas PD-1 expression in tumor cells was not significantly associated with pT/pN stage. In addition, there were no statistically significant associations between PD-1/PD-L1 expression in tumor cells or tumor-infiltrating lymphocytes/macrophages versus patient age, preoperative prostate-specific antigen level, or Gleason score. Kaplan-Meier analysis coupled with log-rank test further revealed no significant associations between PD-1/PD-L1 expression in tumor cells (P = .619/P = .315), tumor-infiltrating lymphocytes/macrophages (P = .954/P = .155), or either or both of them (P = .964/P = .767) versus disease recurrence after radical prostatectomy.PD-1/PD-L1 expression was detected in a subset of prostate cancers. In particular, PD-L1 expression was considerably up-regulated in nonorgan-confined tumors. However, PD-1/PD-L1 expression in our TMA was found to be not very helpful in predicting tumor recurrence in prostate cancer patients who underwent radical prostatectomy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno B7-H1/imunologia , Biomarcadores , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Análise Serial de Tecidos
3.
Medicine (Baltimore) ; 98(39): e17231, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574833

RESUMO

Plasma levels of soluble PD-L1 (sPD-L1) have been reported to be an independent prognostic factor in many malignant tumors. The expression of sPD-L1 in nasopharyngeal carcinoma (NPC) has not been reported. The purpose of this study was to evaluate the expression of sPD-L1 and analyze its correlation with clinical characteristics in patients with NPC.Thirty-five patients with stage I-IVa NPC were included. Plasma samples were obtained pretreatment. The sPD-L1 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The correlations of sPD-L1 expression with clinical parameters and laboratory data were analyzed.sPD-L1 was detected in 35 plasma samples, the mean sPD-L1 concentration was 45.47 pg/ml. sPD-L1 was significantly higher in stage III-IVa (50.76 ±â€Š28.15 pg/ml) compared to stage I-II (19.87 ±â€Š11.38 pg/ml) (t = 2.618, P = .013). sPD-L1 was also higher in stage N2-3 (52.03 ±â€Š28.98 pg/ml) than that in N0-1 (32.88 ±â€Š23.75 pg/ml) (t = 2.096, P = .046). Univariate analysis identified that sPD-L1 level positively correlated with clinical stage (r = 0.495, P = .002) and N stage (r = 0.34, P = .046). Multivariate analysis showed the clinical stage was an independent factor affecting sPD-L1 expression.This is the first report to detect sPD-L1 in NPC. The study indicated sPD-L1 is quantifiable, convenient and easy to obtain. sPD-L1 may serve as a useful biomarker for evaluating tumor progression and therapeutic efficacy of NPC.


Assuntos
Antígeno B7-H1/sangue , Carcinoma Nasofaríngeo/sangue , Neoplasias Nasofaríngeas/sangue , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico , Adulto Jovem
4.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 732-736, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594104

RESUMO

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/metabolismo
5.
Anticancer Res ; 39(10): 5531-5539, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570447

RESUMO

BACKGROUND: Possible correlations between the expression of immune checkpoint molecules and prognosis in childhood acute leukemia were investigated. MATERIALS AND METHODS: The expression of programmed-death 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) was determined by flow cytometry on peripheral αß+ and γδ+ T-cells from patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=9) or acute myeloid leukemia (AML) (n=12), and from healthy volunteers (n=7). The expression of programmed-death ligand 1 (PD-L1), B7-1, B7-2, human leukocyte antigen-ABC (HLA-ABC), and herpesvirus-entry mediator (HVEM) ligands was determined on leukemia blasts. RESULTS: PD1 expression on αß+ and γδ+ T-cells was significantly higher in patients with ALL than in those with AML (p=0.0019 and 0.0239, respectively). CTLA-4 expression was moderately higher on αß+ and γδ+ T-cells in ALL (p=0.077 and 0.077, respectively), whereas HLA-ABC expression was significantly higher in AML blast cells (p=0.0182). The expression of CTLA-4 on γδ+ T-cells and the B7-2 ligand on blasts was higher in patients with high-risk ALL (p=0.02 and 0.02, respectively). In AML, PD1 expression on αß+ T-cells was higher in the intermediate-risk group (p=0.05), whereas HVEM expression was significantly higher in the low-risk group (p=0.02). Expression of CTLA-4 on γδ+ T-cells and PD-L1 on blasts were both associated with poor relapse-free survival outcomes in ALL (p=0.049). CONCLUSION: The higher expression of immune checkpoint molecules, in particular, CTLA-4 and PD-L1 are associated with a poorer prognosis in ALL, suggesting that selective use of the immune checkpoint blockade might improve the clinical outcomes in patients with ALL.


Assuntos
Leucemia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Ligantes , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto Jovem
6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(9): 1091-1096, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31657331

RESUMO

OBJECTIVE: To investigate the effect and mechanism of autophagy on the expression of neutrophil programmed death ligand-1 (PD-L1) in mice with sepsis. METHODS: (1) In vivo experiment: male C57BL/6 mice aged 6-8 weeks were divided into sham operation group (Sham group), cecum ligation and perforation (CLP) group, and rapamycin (RAP)+CLP group by random number table with 10 mice in each group. The sepsis model was reproduced by CLP, and the cecum and perforation were not ligated in Sham group, and other operations were the same as CLP group. The mice in RAP+CLP group were intraperitoneally injected with autophagy agonist RAP 4 mg×kg-1×d-1 7 days before modeling, while the mice in Sham group and CLP group were not treated. Lung, liver, spleen and pancreas tissues were harvested for immunohistochemical staining 4 days after the operation, and the infiltration of neutrophils in various organs was observed under light microscope. Meanwhile, the expressions of immunosuppressive molecule PD-L1 and autophagy marker microtubule-associated protein 1 light chain 3 (LC3) in lung neutrophils were determined by immunofluorescence staining. (2) In vitro experiment: mouse bone marrow neutrophils were extracted and re-suspended to 1×1010/L, and they were divided into blank control group (without any treatment), RAP control group (RAP 100 µmol/L), autophagy inhibitor Bafilomycin A1 (Baf) control group (Baf 10 µmol/L), lipopolysaccharide (LPS) stimulation group (LPS 1 mg /L), RAP+LPS group, and Baf+LPS group. The latter two groups were pretreated with 100 µmol/L RAP or 10 µmol/L Baf 30 minutes before LPS stimulation, respectively. The expression of PD-L1 mRNA of neutrophils was determined by reverse transcription-polymerase chain reaction (RT-PCR) at 0, 4, 12 hours after LPS stimulation. At the same time, the expressions of PD-L1, LC3 and p62 at the protein level were determined by Western Blot. RESULTS: (1) In vivo experiment: according to immunohistochemical experiments, a large amount of infiltration of neutrophils in lung, liver, spleen and pancreas was found at 4 hours after CLP. In the immunofluorescence, with the time extension after CLP, the positive expression of LC3 in the lung tissue showed a decreased tendency, and PD-L1 expression was significantly increased. RAP pretreatment could promote the expression of LC3 and reduce the expression of PD-L1 in CLP mice. (2) In vitro experiment: in terms of mRNA levels, with the extension of LPS stimulation time, the expression of PD-L1 mRNA in mouse neutrophils was increased continuously, and peaked at 12 hours, it was significantly higher than that in the blank control group (2-ΔΔCT: 72.2±10.0 vs. 13.0±0.8, P < 0.01). Compared with LPS stimulation group, the expression of PD-L1 mRNA in RAP+LPS group was significantly down-regulated [12-hour PD-L1 mRNA (2-ΔΔCT): 47.4±7.3 vs. 72.2±10.0, P < 0.01]. In Baf+LPS group, PD-L1 mRNA expression was significantly up-regulated as compared with that in LPS stimulation group [12-hour PD-L1 mRNA (2-ΔΔCT): 109.1±7.4 vs. 72.2±10.0, P < 0.01]. At the protein levels, at 4 hours after LPS stimulation, the positive expressions of PD-L1, LC3 and p62 were increased significantly as compared with those in the blank control group, and PD-L1 and p62 were increased continuously with time. Compared with the LPS stimulation group, the expressions of PD-L1 and p62 in the RAP+LPS group were significantly down-regulated, while the expression of LC3 was continually increased, indicating that the level of autophagy was increased, and autophagy was circulated smoothly. On the contrary, the expressions of PD-L1, LC3 and p62 in the Baf+LPS group were significantly up-regulated, indicating that the binding of autophagy and lysosome was blocked, and autophagy was not smooth. CONCLUSIONS: In sepsis, the infiltration of neutrophils in all organs increased, and the expression of PD-L1 of neutrophils in lungs was increased significantly, while the expression level of autophagy was decreased. The expression of PD-L1 stimulated by LPS can be inhibited by autophagy agonists, and promoted by autophagy inhibitors. PD-L1 has a negative regulatory effect on sepsis. It can reduce the expression of PD-L1 molecule in sepsis by targeting autophagy, so as to improve sepsis.


Assuntos
Autofagia , Sepse , Animais , Antígeno B7-H1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neutrófilos
7.
Anticancer Res ; 39(10): 5789-5795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570483

RESUMO

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. PATIENTS AND METHODS: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. RESULTS: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). CONCLUSION: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.


Assuntos
Antígeno B7-H1/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncogenes/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
8.
Cancer Immunol Immunother ; 68(9): 1537-1545, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482306

RESUMO

PURPOSE: To evaluate the clinical-pathological and prognostic significance of the circulating PD-L1 level in patients with surgically treated NSCLC, by combining data for PD-L1 expression with other immune-related markers and tumor metabolism. METHODS: Overall, 40 patients with resected NSCLC (stage Ia-IIIa) who had preoperative blood storage and underwent staging PET/CT were enrolled for the study. In all cases, we determined plasma levels of PD-L1 (pg/ml), immune-reactive areas (IRA %) covered by CD3, CD68, CD20, CD8, PD-1, and PD-L1 in the tumor specimen, and metabolic parameters on PET, i.e., SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Variables were statistically analyzed to establish their association with disease-free survival (DFS). RESULTS: The circulating levels of PD-L1 in the bloodstream could be determined in 38/40 (95%) samples. The mean and median expression levels were 34.86 pg/ml and 24.83 pg/ml, respectively. We did not find any statistically significant correlation between circulating PD-L1 and tissue expression of PD-L1/PD-1. Some mild degree of positive correlation was determined between tissue PD-L1 and SUVmax (ρ = 0.390; p = 0.0148). Hierarchical clustering combining circulating, tissue, and metabolic parameters identified clusters with high metabolic tumor burden or high expression of plasma PD-L1 levels (Z score ≥ 2) as having a poor DFS (p = 0.033). The multivariate analysis detected stage and metabolism (i.e., SUVmax and SUVpeak) as independent prognostic factors for DFS. CONCLUSION: Plasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical-pathological parameters, allow for the identification of clusters with different outcomes.


Assuntos
Antígeno B7-H1/metabolismo , Proteínas Sanguíneas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Proteínas Sanguíneas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral
9.
Cancer Immunol Immunother ; 68(9): 1501-1513, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489465

RESUMO

INTRODUCTION: Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis. METHODS: Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation. RESULTS: Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression. CONCLUSIONS: The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.


Assuntos
Neoplasias Encefálicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/secundário , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Células Cultivadas , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Regulação para Cima
10.
Urologiia ; (4): 51-57, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31535805

RESUMO

A wide range of variables are associated with poor long-term outcomes of radical treatment in patients with prostate cancer (PCa). Expression of the programmed death-1 ligand 1 (PD-L1) in tumor might be a potential novel marker for PCa. AIM: to evaluate the influence of PD-L1 expression status in tumor cells on long-term results of radical treatment in patients with PCa. MATERIALS AND METHODS: a total of 45 patients with pathologically-proven PCa who undergone radical treatment and followed at N.N. Blokhin National Medical Research Center of Oncology were retrospectively analyzed. In all cases PD-L1 expression in tumor cells was evaluated by immunohistochemical studies of paraffin block sections obtained under direct control of pathologist. Positive expression of PD-L1(+) was defined as expression level in tumor cells more or equal 1%, while hyperexpression was diagnosed when expression level L1 more or equal 5%. RESULTS: PD-L1 expression and hyperexpression in tumor cells were identified in 8 (17.8%) and 6 (13.3%) cases. Median metastasis-free survival in patients with positive PD-L1 expression was 48.918 months (95% CI 42.523-55.313) and was less than in patients with negative PD-L1 expression (68.033 months, 95% CI 48.242- 87.824, p=0.090). Cancer-specific survival in patients with negative PD-L1 expression was significantly longer compared to patients with positive expression (p=0.05) and hyperexpression (p=0.024) of PD-L1 in tumor cells. Multivariate Cox analysis confirmed independent predictive value of positive expression and hyperexpression of PD-L1 in tumor cells for metastasis-free survival (HR 3.461, 95% CI 1.171-10.228, p=0.025, and HR 3.916, 95% CI 1.129-13.591, p=0.032) and cancer-specific survival (HR 7.65, 95% CI 0.69-84.51, p=0.097, and HR 9.73, 95% CI 0.87-108.78, p=0.065). CONCLUSION: According to our study and published data, positive PD-L1 expression in tumor cells is associated with poor prognosis of PCa. Given the lack of association of PD-L1 expression in tumor cells with the routine clinical and pathological characteristics of the disease, it seems reasonable to include the status of PD-L1 expression in the current predictive nomograms for patients with PCa. The results may indicate the potential benefits of developing personalized approaches to PCa treatment, particularly with targeting a PD-L1/PD-1 signaling pathway in tumor cells.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Próstata , Humanos , Masculino , Prognóstico , Estudos Retrospectivos
11.
Anticancer Res ; 39(9): 4737-4742, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519573

RESUMO

BACKGROUND/AIM: There are several unresolved issues regarding the combined treatment with an immune checkpoint inhibitor and anti-angiogenic agent for renal cell carcinoma (RCC) patients. The purpose of this study was to address the inhibitory effects of programmed death-ligand 1 (PD-L1) expression on growth and sensitivity to sunitinib in the mouse RCC RenCa model. MATERIALS AND METHODS: We established RenCa/sh-PD-L1 by transfecting RenCa cells with a plasmid carrying a short hairpin RNA targeted against PD-L1. The growth pattern of RenCa/sh-PD-L1 with or without sunitinib was compared to that of RenCa cells transfected with control plasmid alone (RenCa/Co). RESULTS: No significant difference in growth or sensitivity to sinitinib was noted between RenCa/sh-PD-L1 and RenCa/Co cells in vitro. The tumor volume in mice subcutaneously injected with RenCa/sh-PD-L1 was significantly smaller than that with RenCa/Co. Treatment of mice bearing each tumor with sunitinib resulted in a significant reduction of the RenCa/sh-PD-L1 tumor compared to the RenCa/Co tumor. Moreover, infiltration by CD8+ T cells of RenCa/sh-PD-L1 tumors was significantly higher than that of RenCa/Co tumors, irrespective of treatment with sunitinib. CONCLUSION: Suppressed expression of PD-L1 could increase tumor-infiltrating CD8+ T cells and result in growth inhibition as well as enhanced sensitivity to sunitinib in the RenCa model.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , RNA Interferente Pequeno/genética , Sunitinibe/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Carga Tumoral/efeitos dos fármacos
12.
Anticancer Res ; 39(9): 5195-5201, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519633

RESUMO

BACKGROUND/AIM: Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients. MATERIALS AND METHODS: A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment. RESULTS: Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05). CONCLUSION: sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/sangue , Biomarcadores Tumorais , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Resultado do Tratamento
13.
Internist (Berl) ; 60(10): 1021-1031, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31486857

RESUMO

In pathological diagnostics, monoclonal antibodies (mAb) are mainly used for immunhistochemical analysis. After an initial histological evaluation, a precise panel of antibodies is selected in order to stain the slides by using an indirect immune method. The most frequent issues include localisation of the primary tumor in cases of metastases, determination of undifferentiated tumors, subtyping of lympho-proliferative diseases and soft tissue tumors, as well as the assessment of proliferation via Ki-67. Increasing importance in mAb-based diagnostics is attributed to the analysis of predictive biomarkers such as hormone receptors, mismatch repair proteins (MMR) and programmed death ligand 1 (PD-L1). Their evaluation is performed by using different scores, which the clinical physician needs to be aware of due to their direct therapeutic implications.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Biomarcadores Tumorais/metabolismo , Reparo de Erro de Pareamento de DNA , Imuno-Histoquímica/métodos , Neoplasias/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias/genética , Neoplasias/metabolismo
14.
Pol J Pathol ; 70(2): 139-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556565

RESUMO

We report on a breast carcinoma with medullary features diagnosed by core needle biopsy in a 72-year-old woman. Both the primary tumour and its fine needle aspiration-proven, rapidly growing axillary metastasis regressed completely in less than 2 months, by the time surgery was performed. The biopsy of the primary tumour demonstrated a dense stromal infiltrate of CD8+/granzyme B+ activated cytotoxic T-cells suggestive of a robust antitumour immune response. Paradoxically, both tumour cells and tumour infiltrating immune cells demonstrated a diffuse PD-L1 expression, revealing that antitumour immune response has the ability to spontaneously overcome inhibitory mechanisms induced by cancerous growth.


Assuntos
Carcinoma/diagnóstico , Metástase Linfática , Neoplasias de Mama Triplo Negativas/diagnóstico , Idoso , Antígeno B7-H1/metabolismo , Biópsia por Agulha Fina , Biópsia com Agulha de Grande Calibre , Carcinoma/imunologia , Feminino , Humanos , Linfócitos do Interstício Tumoral , Linfócitos T Citotóxicos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia
15.
Cancer Invest ; 37(9): 463-477, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31490702

RESUMO

The associations of the immunological status of the pancreatic ductal adenocarcinoma (PDA) microenvironment with prognosis were assessed. A high tumor-infiltrating lymphocyte (TIL) density was associated with a better prognosis. Importantly, even with a high density of TILs, the PDA cells with programed cell death-ligand 1 (PD-L1) expression showed a worse prognosis than the patients with negative PD-L1 expression. A significant association between a better prognosis and a tumor microenvironment with a high TIL density/negative PD-L1 expression was observed. Assessments of a combined immunological status in the tumor microenvironment may predict the prognosis of PDA patients following surgical resection.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Prognóstico , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral
16.
Cancer Immunol Immunother ; 68(10): 1573-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31511925

RESUMO

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.


Assuntos
Antígeno B7-H1/fisiologia , Fibromatose Agressiva/imunologia , Tolerância Imunológica , Adolescente , Adulto , Idoso , Antígenos CD20/análise , Ligante CD27/análise , Feminino , Fibromatose Agressiva/patologia , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral , Adulto Jovem
17.
Cancer Sci ; 110(10): 3068-3078, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432577

RESUMO

The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin-17 (IL-17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL-17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL-17-producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi-color flow cytometry (Th17: P < 0.0001 and P = 0.0002, respectively; γδT17: P = 0.0020 and P = 0.0084, respectively). IL-17 mRNA level was elevated in PBMC of ovarian cancer patients (P = 0.0029), as measured by RT-PCR. The neutrophil-to-lymphocyte ratio, which is a prognostic biomarker of ovarian cancer, correlated with Th17 occupancy ratio in patients (P = 0.0068). We found that programmed cell death 1 ligand 1 expression and its associated factors (IL-6 and phospho-signal transducer and activator of transcription 3) were induced by IL-17 in an ovarian cancer cell line. These results suggest that increased Th17 counts and IL-17 level, which correlated with high neutrophil-to-lymphocyte ratio and programmed cell death 1 ligand 1 expression, are potential biomarkers for poor prognosis in ovarian cancer and likely indications for application of programmed cell death 1 ligand 1 pathway inhibitors.


Assuntos
Antígeno B7-H1/genética , Neoplasias do Endométrio/genética , Interleucina-16/metabolismo , Interleucina-17/genética , Neoplasias Ovarianas/genética , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias do Endométrio/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-17/metabolismo , Linfócitos Intraepiteliais/metabolismo , Neoplasias Ovarianas/imunologia , Fosforilação , Prognóstico , Células Th17/metabolismo , Regulação para Cima
18.
Life Sci ; 233: 116713, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386875

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide. Treatment with immunotherapy has made a significant impact on the outcomes for those patients suffering from lung cancer and its usage is currently an established treatment modality. Immune checkpoint inhibition that has blocking antibodies which target cytotoxic T-lymphocyte antigen-4 (CTLA-4) along with the programmed cell death protein 1 (PD-1) pathway [programmed death - 1/programmed death-ligand 1 (PD-L1)] have shown promising results for numerous malignancies. Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies while atezolizumab, avelumab, and durvalumab are approved as PD-L1 blocking antibodies by 'US Food and Drug Administration'. Immune checkpoint inhibitors have been found to statistically improve the survival of patients with lung cancer and have emerged as the primary immunotherapy in lung cancer and have changed the treatment paradigm for advanced disease. Despite such benefits, treatment with immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse effects or side effects. Also, resistance is routinely developing in patients treated with immune checkpoint inhibitors. The current review provides an overview of immune checkpoint inhibitor treatment in lung cancer, its resistance, and adverse effects.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Prognóstico
19.
Cancer Immunol Immunother ; 68(9): 1443-1454, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31444607

RESUMO

Immunotherapy is effective in head and neck squamous cell carcinoma (HNSCC), but only a minority of patients responds to immune checkpoint blockade (ICB). To contribute to a better understanding of the underlying immune biology, we combined histomorphological evaluation and molecular analysis of the HNSCC immune microenvironment in the TCGA cohort. Analyzing digital HE-stained slides, a method for classification of tumor infiltrating lymphocytes (TILs) in the intra-epithelial compartment (ieTILs, present vs. absent) and the stromal compartment (strTILs, high vs. low) was established. We also analyzed the abundance of eight immune cell populations (estimated from RNAseq data) and PD-L1 mRNA expression. Status of ieTILs and status of strTILs were concordant for 61%, but discordant for 39% of tumors. In univariate survival analysis, ieTILs were a positive prognostic marker for DFS in the study cohort (HR = 0.66, p = 0.015) and in the HPV- subcohort (HR = 0.68, p = 0.04), but not in the HPV + subcohort. T cells were a positive prognostic marker for DFS in the study cohort (HR = 0.80, p = 0.03) and in the HPV + subcohort (HR = 0.20, p = 0.001), but not in the HPV- subcohort. In univariate survival analysis, PD-L1 mRNA expression was neither associated with DFS nor with OS. However, in bivariate and multivariate analyses including both PD-L1 mRNA levels and T cells, PD-L1 was a negative prognostic marker of DFS and OS, while T cells remained a positive prognostic marker. In conclusion, ieTILs and strTILs were non-redundant biomarkers in HNSCC and should be evaluated separately. The identified prognostic markers should be evaluated for predictivity in ICB-treated patients.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/imunologia , Células Epiteliais/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Células Estromais/patologia , Antígeno B7-H1/genética , Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de RNA , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral
20.
Cancer Sci ; 110(10): 3244-3254, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368625

RESUMO

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8+ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos CD8/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
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