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1.
Lancet Oncol ; 21(10): 1283-1295, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002436

RESUMO

BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. FUNDING: F Hoffman-La Roche.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Resultado do Tratamento
2.
Front Immunol ; 11: 1870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983106

RESUMO

Coronavirus disease 2019 (COVID-19) which is caused by the novel SARS-CoV-2 virus is a severe flu-like illness which is associated with hyperinflammation and immune dysfunction. The virus induces a strong T and B cell response but little is known about the immune pathology of this viral infection. Acute Plasmodium falciparum malaria also causes acute clinical illness and is characterized by hyperinflammation due to the strong production of pro-inflammatory cytokines and a massive activation of T cells. In malaria, T cells express a variety of co-inhibitory receptors which might be a consequence of their activation but also might limit their overwhelming function. Thus, T cells are implicated in protection as well as in pathology. The outcome of malaria is thought to be a consequence of the balance between co-activation and co-inhibition of T cells. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8+ and CD4+ T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. falciparum infected patients and n = 13 healthy controls. Overall, acute COVID-19 and malaria infection resulted in a comparably elevated activation and altered differentiation status of the CD8+ and CD4+ T cell populations. T effector cells of COVID-19 and malaria patients showed higher frequencies of the inhibitory receptors T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene-3 (LAG-3) which was linked to increased activation levels and an upregulation of the transcription factors T-bet and eomes. COVID-19 patients with a more severe disease course showed higher levels of LAG-3 and TIM-3 than patients with a mild disease course. During recovery, a rapid normalization of these inhibitory receptors could be observed. In summary, comparing the expression of different co-inhibitory molecules in CD8+ and CD4+ T cells in COVID-19 vs. malaria, there is a transient increase of the expression of certain inhibitory receptors like LAG-3 and TIM-3 in COVID-19 in the overall context of acute immune activation.


Assuntos
Antígenos CD/metabolismo , Betacoronavirus/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Ativação Linfocitária/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/isolamento & purificação , Pneumonia Viral/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Doença Aguda , Adulto , Idoso , Células Cultivadas , Estudos de Coortes , Infecções por Coronavirus/virologia , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/metabolismo , Índice de Gravidade de Doença
3.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
4.
BMC Infect Dis ; 20(1): 590, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778058

RESUMO

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Fígado/patologia , Polietilenoglicóis/uso terapêutico , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
5.
Nat Commun ; 11(1): 3998, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778730

RESUMO

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunidade Inata/imunologia , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Células Th2/metabolismo , Transcriptoma
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.
PLoS One ; 15(8): e0237646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845913

RESUMO

Tumor antigen-primed CD8 T cells differentiate into effector T cells that kill tumor cells rapidly, whereas durable responses of CD8 T cells are required to cope with long-lasting tumor growth. However, it is not well known how persisting CD8 T cells are generated. In this study, we analyzed CD8 T cells primed by antigens in tumor-draining lymph nodes and found that CD8 T cells first differentiated into a CD62L-intermediate (CD62Lint) stage upon antigen stimulation. These cells gave rise to tumor-infiltrating CD62L-CD44high Bcl6- effector T cells and CD62L+CD44highBcl6+ memory-like T cells. Memory-like T cells within the tumor expressed CD127, CXCR3 and had the potential to proliferate significantly when they were transferred into tumor-bearing mice. Bcl6 expression in these T cells was critical because Bcl6-/-CD62L+CD44highCD8T cells within the tumor were defective in expansion after secondary transfer. Taken together, our findings show that CD62L+CD44highBcl6+ cells are generated from highly proliferating CD62Lint T cells and retain high proliferative potential, which contributes to replenishment of effector T cells within the tumor.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Lewis/patologia , Memória Imunológica/imunologia , Selectina L/metabolismo , Melanoma Experimental/patologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Diferenciação Celular , Feminino , Selectina L/genética , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Células Tumorais Cultivadas
8.
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
10.
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
11.
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
12.
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
13.
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
14.
Proc Natl Acad Sci U S A ; 117(25): 14331-14341, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513686

RESUMO

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately four new cases per 100,000 persons per year. Standard treatment for AML consists of induction chemotherapy with remission achieved in 50 to 75% of cases. Unfortunately, most patients will relapse and die from their disease, as 5-y survival is roughly 29%. Therefore, other treatment options are urgently needed. In recent years, immune-based therapies have led to unprecedented rates of survival among patients with some advanced cancers. Suppression of T cell function in the tumor microenvironment is commonly observed and may play a role in AML. We found that there is a significant association between T cell infiltration in the bone marrow microenvironment of newly diagnosed patients with AML and increased overall survival. Functional studies aimed at establishing the degree of T cell suppression in patients with AML revealed impaired T cell function in many patients. In most cases, T cell proliferation could be restored by blocking the immune checkpoint molecules PD-1, CTLA-4, or TIM3. Our data demonstrate that AML establishes an immune suppressive environment in the bone marrow, in part through T cell checkpoint function.


Assuntos
Medula Óssea/metabolismo , Leucemia Mieloide Aguda/metabolismo , Linfócitos T/metabolismo , Microambiente Tumoral/fisiologia , Medula Óssea/imunologia , Antígeno CTLA-4/metabolismo , Proliferação de Células , Citocinas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia
16.
Life Sci ; 256: 117923, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522567

RESUMO

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metformina/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
17.
PLoS One ; 15(6): e0234778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569289

RESUMO

Acute graft-versus-host-disease (GVHD), limits the use of hematopoietic cell transplant (HCT) to treat a variety of malignancies. Any new therapeutic approach must satisfy three requirements: 1) Prevent GVHD, 2) Maintain anti-pathogen immunity, and 3) Maintain anti-tumor immunity. In prior studies we have shown that the selective photosensitizer 2-Se-Cl eliminates highly alloreactive lymphocytes from the graft prior to HCT preventing GVHD and that antiviral immune responses were preserved following incubation with 2-Se-Cl. In this report, we investigated whether 2-Se-Cl treatment preserves antitumor immunity, and then used high dimensional flow cytometry to identify the determinants of successful immune reconstitution. Donor C57BL/6 splenocytes were cocultured for 4 days with irradiated BALB/c splenocytes and then exposed to 2-Se-Cl. Photodepletion (PD)-treated splenocytes were then infused into lethally irradiated BALB/c mice inoculated with A20 leukemia/lymphoma cells. Recipient mice that received PD-treated splenocytes survived > 100 days without evidence of GVHD or leukemia. In contrast, mice that did not receive PD-treated cells at time of HCT died of leukemia progression. Multiparameter flow cytometry of cytokines and surface markers on peripheral blood samples 15 days after HCT demonstrated unique patterns of immune reconstitution. We found that before clinical disease onset GVHD was marked by functionally exhausted T cells, while tumor clearance and long-term survival were associated with an expansion of polyfunctional T cells, monocytes, and DCs early after transplantation. Taken together these results demonstrate that 2-Se-Cl photodepletion is a new treatment that can facilitate HCT by preventing GVHD while preserving antiviral and anti-tumor immunity.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Fármacos Fotossensibilizantes/farmacologia , Compostos de Selênio/farmacologia , Animais , Antígeno CTLA-4/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Feminino , Leucemia/imunologia , Leucemia/terapia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
18.
Life Sci ; 256: 117899, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504749

RESUMO

Cancer immunotherapy is a growing field nowadays. Among different molecular pathways, PD-1/PD-L1 signaling pathway plays a significant role in the regulation of immune responses. It has been reported that stimulation of PD-1/PD-L1 axis is correlated with T cell exhaustion, T cell apoptosis, and their reduced capability in proliferation. PD-1/PD-L1 axis provides a condition for immune evasion of cancer cells and interferes with anti-tumor immunity. Much attention has been directed towards targeting PD-1/PD-L1 axis in cancer immunotherapy. It seems that identification of upstream modulators of this axis can broaden our understanding to develop novel anti-tumor drugs for cancer immunotherapy. MicroRNAs (miRs) and long non-coding RNAs (lncRNAs) are key subcategories of non-coding RNAs, since they can regulate various biological processes by targeting different molecular pathways. In this review, we demonstrate that onco-suppressor miRs and lncRNAs inhibit PD-1/PD-L1 axis to provide anti-tumor immunity and in this way, other molecular pathways such as STAT, ZEB, PI3K/Akt and so on may be targeted. In contrast, oncogene miRs and lncRNAs induce PD-1/PD-L1 axis. Identification of miR/PD-1 and lncRNA/PD-1 signaling pathways can help us in finding an effective drug for cancer immunotherapy, and can direct us towards genetic manipulation of the aforementioned pathways.


Assuntos
Antígeno B7-H1/metabolismo , MicroRNAs/genética , Neoplasias/genética , Neoplasias/terapia , Receptor de Morte Celular Programada 1/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Animais , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética
19.
Crit Rev Oncol Hematol ; 151: 102965, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32442903

RESUMO

Glioblastoma (GBM) is the most common malignant tumour in the brain, and current treatments are not curative and cannot control recurrence. This limitation indirectly places immunotherapy at the focus of translational GBM research. Many studies on the PD-1/PD-L1 axis in GBM are ongoing, and the immunosuppressive mechanism of PD-1/PD-L1 in GBM is different from that in other solid tumours. This review focuses on the effect of the PD-1/PD-L1 axis on infiltrating immune cells in the suppressive GBM immune microenvironment and summarizes the recent progress in PD-1/PD-L1 axis-related therapies reported in preclinical and clinical GBM studies, providing a reference for the systematic study of PD-1/PD-L1 axis-related anti-GBM immunity.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
20.
Oncology ; 98(7): 501-511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32380498

RESUMO

INTRODUCTION: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. METHODS: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. RESULTS: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. CONCLUSIONS: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.


Assuntos
Antígeno B7-H1/genética , Antígenos CD8/genética , Expressão Gênica/imunologia , Receptor de Morte Celular Programada 1/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/imunologia , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
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