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1.
N Engl J Med ; 383(14): 1328-1339, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997907

RESUMO

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida
2.
Life Sci ; 259: 118389, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898522

RESUMO

AIMS: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Hipóxia/etiologia , Neoplasias Pulmonares/metabolismo , Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade
3.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Zhonghua Bing Li Xue Za Zhi ; 49(10): 999-1002, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-32992412

RESUMO

Objective: To study the expression of phosphates signal transducer and activator of transcription 3 (pSTAT3) and programmed death ligand-1 (PD-L1) in extranodal NK/T cell lymphomas (ENKTCL) and the relationships of pSTAT3 and PD-L1 expression with the clinicopathological characteristics and prognosis of ENKTCL. Methods: Fifty-one cases of ENKTCL diagnosed at Guangdong Provincial People's Hospital from June 2015 to February 2019 were included in the study. The expression of pSTAT3 and PD-L1 was examined using immunohistochemistry. Results: There were 35 males and 16 females, ranging from 18 to 85 years old with a median age of 47 years. The positive rates of pSTAT3 and PD-L1 expression were 68.6% (35/51) and 76.5% (39/51), respectively. pSTAT3 expression was correlated with PD-L1 expression (P=0.033,R=0.322), while there were no associations of pSTAT3 and PD-L1 expression with the clinicopathological characteristics of ENKTCL, including age, sex, clinical site, B symptom, Ann Arbor stage, LDH value, EBV DNA load of peripheral blood and international proliferation index score. Kaplan-Meier survival analysis showed the prognoses of the pSTAT3 and PD-L1 positive groups were slightly better than the respective negative groups, but the differences were not significantly (P>0.05). Conclusions: pSTAT3 is highly expressed in extranodal NK/T cell lymphoma and related to the expression of PD-L1, which provides a potential target and rationale for combinations of targeted therapies and immune checkpoint blockade inhibitors in the treatment of ENKTCL.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma Extranodal de Células T-NK , Fator de Transcrição STAT3/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos , Prognóstico , Adulto Jovem
5.
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
6.
Life Sci ; 259: 118297, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822718

RESUMO

Triple-negative breast cancer (TNBC) is heterogeneous cancer with poor prognosis among the other breast tumors. Rapid recurrence and increased progression rate could be reasons for the poor prognosis of this type of breast cancer. Recently, because of the lack of specific targets in multiple cancer treatment, immune checkpoint blockade therapies with targeting PD-1/PD-L1 axis have displayed significant advances and improved survival. Among different types of breast cancers, TNBC is considered more immunogenic with high T-cell and other immune cells infiltration compared to other breast cancer subtypes. This immunogenic characteristic of TNBC is a beneficial marker in the immunotherapy of these tumors. Clinical studies with a focus on immune checkpoint therapy have demonstrated promising results in TNBC treatment. In this review, we summarize clinical trials with the immunotherapy-based treatment of different cancers and also discuss the interaction between infiltrating immune cells and breast tumor microenvironment. In addition, we focus on the signaling pathway that controls PD-L1 expression and continues with CAR T-cell therapy and siRNA as novel strategies and potential tools in targeted therapy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo
7.
Science ; 369(6506): 993-999, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820126

RESUMO

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/farmacologia , Animais , Antígeno B7-H1/metabolismo , Materiais Biomiméticos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Cristalografia por Raios X , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Nucleotídeos Cíclicos/química , Conformação Proteica/efeitos dos fármacos
8.
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
9.
Cancer Invest ; 38(7): 406-414, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32762373

RESUMO

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida
10.
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
11.
Life Sci ; 258: 118110, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32698074

RESUMO

Incapacitated immune system is a characteristic hallmark of solid tumors. Immune system within a tumor undergoes an imbalance in cellular dispersion and functionality. Effector cells are precluded from the invasive margin of tumor; instead, immune suppressor cells are present at high fractions. Conditions in the tumor microenvironment (TME) like altered metabolism, chronic hypoxia and chronic inflammation are the known predisposing factors, implicated in the immune malfunctioning. Deficiency of innate immune sensing mediated by checkpoint receptors including programmed death-1 receptor (PD-1), CTL-associated antigen-4 (CTLA-4) hijacked by tumor cells takes a major part of the blame, requiring a need for appropriate strategies in order to bring back the balance in the immune system. Immune checkpoint inhibitor (ICI) therapy has been in the eye of the current research rendering promising results. The story is not, however, that easy in which it is not so effective for Cold tumors, it may cause severe adverse effects, and that patients may acquire resistance to such therapy; this requires for updating the current knowledge about the immune ecosystem, using tumor type dependent dose calculation and exploiting proper adjuvants in order for evolving desired responses.


Assuntos
Evasão da Resposta Imune , Neoplasias/imunologia , Animais , Antígeno B7-H1/metabolismo , Carcinogênese/patologia , Humanos , Imunoterapia , Neoplasias/terapia , Microambiente Tumoral/imunologia
12.
Anticancer Res ; 40(7): 4001-4010, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620644

RESUMO

BACKGROUND/AIM: This study was conducted to comprehensively evaluate programmed cell death ligand 1 (PD-L1) expression, and analyze the clinical and prognostic implications of PD-L1 expression in oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: We evaluated the expression of PD-L1 using the antibodies SP263 and SP142 in 106 patients with OPSCC, using immunohistochemistry. PD-L1 expression was subdivided into tumor cell score (TC), immune cell score (IC), and combined score (CS). Correlations between each PD-L1 expression and HPV status, clinicopathological features, and survival were analyzed. RESULTS: The expression levels of PD-L1 SP263 and SP142 were significantly correlated. High PD-L1 SP263 TC and CS and SP142 IC and CS were associated with HPV positivity. PD-L1 expression showed no effect on survival in all patients' group. However, in the subgroup analysis, high TC and CS of both PD-L1 SP263 and SP142 were correlated with shorter time to recurrence in the HPV positive group. CONCLUSION: High expression of PD-L1 was associated with HPV positivity in OPSCC. In addition, high expression of PD-L1 might suggest a poorer outcome, especially in the HPV positive subgroup. PD-L1 could be a useful predictive and prognostic biomarker in OPSCC.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores/metabolismo , Neoplasias Orofaríngeas/metabolismo , Infecções por Papillomavirus/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
13.
Anticancer Res ; 40(7): 4123-4129, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620661

RESUMO

BACKGROUND/AIM: The efficacy of pembrolizumab for intrahepatic cholangiocellular carcinoma (IHCCC) is not widely reported. CASE REPORT: We began pembrolizumab treatment in a 69-year-old male with recurrent IHCCC at 18 months after his surgery because of the proven microsatellite instability (MSI)-high status. The patient had partial response, with an 82.5% reduction at the end of 18 courses. Immunostaining of the primary tumor revealed intra-tumoral infiltration of both PD-1+ and CD8+ T cells, and a low expression of PD-L1. CONCLUSION: Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Idoso , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/cirurgia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Colangiocarcinoma/imunologia , Colangiocarcinoma/cirurgia , Humanos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Resultado do Tratamento
14.
Nat Commun ; 11(1): 3747, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719340

RESUMO

Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.


Assuntos
Proteína BRCA1/genética , Mutação/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteína BRCA1/deficiência , Estudos de Coortes , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia
15.
Nature ; 584(7820): 291-297, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32728216

RESUMO

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein-for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2 and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5 and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins-the products of 40% of all protein-encoding genes7-are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide ligands that are agonists of the cation-independent mannose-6-phosphate receptor (CI-M6PR). We use LYTACs to develop a CRISPR interference screen that reveals the biochemical pathway for CI-M6PR-mediated cargo internalization in cell lines, and uncover the exocyst complex as a previously unidentified-but essential-component of this pathway. We demonstrate the scope of this platform through the degradation of therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics.


Assuntos
Espaço Extracelular/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo , Proteólise , Proteínas Recombinantes de Fusão/metabolismo , Animais , Anticorpos/química , Anticorpos/metabolismo , Antígenos CD/metabolismo , Apolipoproteína E4/metabolismo , Antígeno B7-H1/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Receptores ErbB/metabolismo , Feminino , Glicopeptídeos/síntese química , Glicopeptídeos/metabolismo , Humanos , Ligantes , Proteínas de Membrana/química , Camundongos , Domínios Proteicos , Transporte Proteico , Receptor IGF Tipo 2/metabolismo , Receptores da Transferrina/metabolismo , Proteínas Recombinantes de Fusão/síntese química , Proteínas Recombinantes de Fusão/química , Solubilidade , Especificidade por Substrato
16.
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
17.
Life Sci ; 257: 118057, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634427

RESUMO

AIMS: We set about to investigate the potential role of microRNA-155-5p (miR-155-5p) in the development of immune thrombocytopenia (ITP), an idiopathic deficiency of blood platelets. MAIN METHODS: Initially, RT-qPCR and Western blot analyses were carried out to determine the expression of miR-155-5p and SOCS1 in peripheral blood mononuclear cells (PBMCs) and macrophages from ITP patients. We undertook gain- and loss- function methods by transfection of macrophages and PBMCs with treated plasmids. The expression patterns of platelet-related factors were measured by ELISA, and the expressions of PD1, PDL1, and macrophage M2 marker CD206 and CD86 were also measured. The relationship between miR-155-5p and SOCS1 was determined using the dual-luciferase reporter gene assay. We also established an ITP mouse model to explore the roles of miR-155-5p and SOCS1 in vivo. KEY FINDINGS: miR-155-5p was up-regulated, while SOCS1 was down-regulated in PBMCs and macrophages from ITP patients. SOCS1 was indicated as a target of miR-155-5p. Inhibition of miR-155-5p or up-regulation of SOCS1 facilitated macrophage M2 polarization as demonstrated by an increased M2/M1 ratio and suppressed expression of platelet-related factors. Furthermore, silencing of SOCS1 promoted ITP progression through blocking the PD1/PDL1 pathway, whilst upregulation of miR-155-5p remarkably increased the platelet abundance and suppressed SOCS1 expression in ITP model mice. SIGNIFICANCE: Silencing of miR-155-5p could promote PD1/PDL1 pathway-mediated macrophage M2 polarization and prevent ITP via up-regulation of SOCS1, thus relieving ITP.


Assuntos
Macrófagos/metabolismo , MicroRNAs/genética , Púrpura Trombocitopênica Idiopática/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno B7-H1/metabolismo , Progressão da Doença , Regulação para Baixo , Feminino , Inativação Gênica , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Púrpura Trombocitopênica Idiopática/fisiopatologia , Regulação para Cima , Adulto Jovem
18.
Life Sci ; 257: 118068, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32653521

RESUMO

AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumour with increasing incidence and high mortality. Liver kinase B1 (LKB1) regulates cellular energy metabolism and cell division and affects immune microenvironment. This study aimed to uncover the underlying function and mechanism of LKB1 in ICC. MAIN METHODS: To determine the correlation between LKB1 levels and clinicopathological features, the expression profile of LKB1 in ICC tissue specimens was examined by qRT-PCR and western blotting. In vitro experiments were conducted to examine the anticancer effect of LKB1 in ICC. Changes in the expression of epithelial-mesenchymal transition (EMT)-associated markers and immune checkpoints were analysed by qRT-PCR, western blotting, immunofluorescence and flow cytometry. The influence of LKB1 on the transcriptional activity of PD-L1 was determined by dual-luciferase reporter assays and IFNγ induction. KEY FINDINGS: LKB1 was expressed at low levels in ICC and tightly associated with poor prognosis. LKB1 knockdown promoted the proliferation, migration, matrix adhesion and EMT of ICC cells. Notably, LKB1 silencing upregulated the surface expression of PD-L1 in ICC cells. Suppressed and mutated LKB1 enhanced the transcriptional activity of PD-L1 in ICC cells, leading to high expression of the immune checkpoint PD-L1. Furthermore, inhibiting LKB1 suppressed ICC cell apoptosis induced by IFNγ. SIGNIFICANCE: By suppressing malignant transformation and the immune checkpoint PD-L1 of cancer cells, LKB1 plays an important role in inhibiting ICC and is a potential target for clinical diagnosis and treatment. This study may provide new strategies for improving the efficiency of cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Colangiocarcinoma/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
19.
Life Sci ; 257: 118117, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32693243

RESUMO

AIMS: B cells can promote or inhibit immune responses against breast cancer. We investigated changes in the frequency of B cells with stimulatory or regulatory capacity in breast tumor draining lymph nodes during cancer progression. MAIN METHODS: We isolated mononuclear cells from fresh axillary lymph nodes (LNs) of 44 patients with breast cancer and stained lymphocytes with antibodies against CD19, CD80, CD86, CD39 and CD73. To assess programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) expression, lymphocytes were briefly stimulated, stained for CD19, PD-1 and PD-L1, and examined with flow cytometry. KEY FINDINGS: The frequency of CD80+ B cells was higher in nonmetastatic lymph nodes, while the percentage of CD86+ B cells showed a positive relationship with higher tumor grade and higher numbers of involved LNs. A small proportion of unstimulated B cells expressed PD-1 or PD-L1 but these molecules were rapidly upregulated on B cells following activation. The frequency of stimulated PD-L1+ B cells showed an inverse association with estrogen and progesterone receptor expression and a nonsignificant positive association with tumor grade. In addition, the percentage of unstimulated PD-1+ B cells was higher in patients with higher-grade tumors. CD73 expression on B cells was associated with lower numbers of involved LNs, and the frequency of CD39+ B cells was higher in patients with larger tumors. SIGNIFICANCE: CD86+, CD39+, PD-1+ and PD-L1+ B cells showed associations with poor prognostic factors, therefore their potential role in the suppression of the immune responses against breast cancer should be evaluated in greater detail.


Assuntos
Subpopulações de Linfócitos B/patologia , Linfócitos B Reguladores/patologia , Neoplasias da Mama/imunologia , Linfonodos/patologia , Adulto , Idoso , Apirase/imunologia , Axila , Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/imunologia , Antígeno B7-2/imunologia , Antígeno B7-H1/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Citometria de Fluxo , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo
20.
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
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