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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.
Yi Chuan ; 41(8): 725-735, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447423

RESUMO

Oropharyngeal cancer is one type of head and neck squamous cell carcinoma that is commonly associated with human papillomavirus (HPV) infection. Its incidence is increasing year by year. However, in the clinical treatment, it is found that the overall prognosis of HPV positive oropharyngeal cancer patients is better than that of HPV negative patients. But till now, the underlying mechanism that leads to this phenomenon has not been fully elucidated. This research analyzed the immune cell infiltration and function, as well as neoantigen loads between HPV positive and negative patients by bioinformatic analysis using the TCGA database, and found that the overall survival rate of HPV positive patients was significantly higher than those in the HPV negative group. Analysis of the relative abundance of immune cells in tumor tissues showed that CD8 + T cells in HPV positive patients were significantly increased compared to those in HPV negative patients, and the expression levels of effector molecules, like IFN-γ and Granzyme B, were significantly upregulated. Meanwhile, the analysis of tumor neoantigen load (TNB) showed that the TNB of HPV positive patients was lower than that of the HPV negative group. This study provides some basic theoretical support for the treating HPV-related oropharyngeal cancer.


Assuntos
Antígenos de Neoplasias/análise , Linfócitos T CD8-Positivos/citologia , Neoplasias Orofaríngeas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Humanos , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Prognóstico
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 552-556, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292060

RESUMO

Objective To investigate the effect of diabetes mellitus on lymphocytes in rheumatic heart valve tissue and its mechanism. Methods Valve tissues of 40 patients undergoing heart valve replacement were collected, including 20 patients in rheumatic heart disease group (without diabetes) and 20 patients in diabetic group (rheumatic heart disease combined with diabetes). In addition, 20 cases of valve tissue from control group were collected. HE staining was used to observe the damage of valve tissue and the area of collagen degeneration. CD4+ T cells, CD8+ T cells, B cells and plasma cells were detected by immunohistochemical staining. Flow cytometry was used to detect the proportion of regulatory T cells (Tregs) in peripheral blood. Results Compared with the rheumatic heart disease group, the damage of valve tissue in the diabetic group was further aggravated, the number of infiltrating inflammatory cells increased, and the area of collagen degeneration was enlarged. Compared with the control group, the number of T cells, CD4+ T cells, CD8+ T cells, B cells and plasma cells in valve tissue of patients with rheumatic heart disease increased significantly. Diabetes mellitus further increased the number of T cells, CD4+ T cells, B cells and plasma cells in valve tissue, but had no significant effect on CD8+ T cells. The proportion of Tregs in the peripheral blood of patients with rheumatic heart disease was significantly reduced. Diabetes mellitus could further reduce the proportion of Tregs. Conclusion The number of T cells, CD4+T cells, B cells and plasma cells in heart valves of rheumatic heart disease patients with diabetes mellitus go up significantly, and Treg ratio goes down.


Assuntos
Linfócitos B/citologia , Linfócitos T CD8-Positivos/citologia , Diabetes Mellitus/patologia , Valvas Cardíacas/citologia , Cardiopatia Reumática/complicações , Linfócitos T Reguladores/citologia , Estudos de Casos e Controles , Humanos
4.
Nature ; 571(7764): 270-274, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207604

RESUMO

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Transcrição Genética
5.
Invest Ophthalmol Vis Sci ; 60(6): 2388-2398, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141610

RESUMO

Purpose: Conjunctival squamous cell carcinoma (SCC), a type of ocular surface neoplasia, is primarily treated by surgical resection and topical immuno- or chemotherapy. Metastatic disease may be treated with systemic chemo- or immunotherapy, albeit with variable response. The purpose of this study was to determine whether immune checkpoint blockade might be considered in the management of conjunctival SCC. Methods: In this retrospective study, we evaluated tumor programmed death-ligand 1 (PD-L1) expression, high-risk human papillomavirus (HPV) status, and immunohistochemical expression of cluster of differentiation 3 (CD3), cluster of differentiation 8 (CD8), and programmed death 1 (PD1) in tumor-associated immune infiltrate in a series of 31 conjunctival SCCs. Results: PD-L1 expression in ≥1% of tumor cells was noted in 14 conjunctival SCCs (47%) and was more prevalent in invasive than in situ SCC and among tumors with higher American Joint Committee on Cancer (AJCC) T category (≥T3 versus ≤T2). The density of CD3-positive T cells was higher in primary than recurrent tumors and higher in invasive than in situ tumors. Density of CD3-positive and CD8-positive T cells was higher in higher AJCC stage tumors. Density of CD8-positive T cells was higher in HPV-positive than HPV-negative tumors. PD-L1 expression correlated with a higher density of CD3-, CD8-, and PD1-positive cells in the tumor-associated immune infiltrate but not with HPV status. Conclusions: Our findings demonstrate that PD-L1 is expressed in almost half of conjunctival SCCs. The density of tumor-associated immune cells correlated with invasive SCC, stage, and HPV status in conjunctival SCC. Our findings support further studies to establish the potential application of immune checkpoint blockade in the management of conjunctival SCC.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias da Túnica Conjuntiva/metabolismo , Infecções por Papillomavirus/complicações , Receptor de Morte Celular Programada 1/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/citologia , Humanos , Estudos Retrospectivos
6.
Cancer Sci ; 110(7): 2100-2109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100180

RESUMO

The presence of interleukin (IL)-17-producing T cells has recently been reported in non-small cell lung cancer (NSCLC) patients. However, the long-term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL-17-producing CD4+ T (Th17), CD8+ T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow-up time was 13.5 months (range 1-87 months). The 3- and 5-year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)-γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5-year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5-year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos T/citologia , Células Th17/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/metabolismo , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Linfócitos T/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/imunologia
7.
J Immunol Res ; 2019: 1418251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061831

RESUMO

The outbreak of avian influenza A (H7N9) virus infection, with a high mortality rate, has caused concern worldwide. Although interleukin-17- (IL-17-) secreting CD4+ T (Th17) and CD8+ T (Tc17) cells have been proven to play crucial roles in influenza virus infection, the changes and roles of Th17 and Tc17 cells in immune responses to H7N9 infection remain controversial. In this study, we found that the frequencies of Th17 and Tc17 cells among human peripheral blood mononuclear cells (PBMCs) as well as IL-17A protein and mRNA levels were markedly decreased in patients with acute H7N9 virus infection. A positive correlation was found between the serum IL-17A level and the frequency of these two cell groups. In vitro infection experiments revealed decreased Th17 and Tc17 cell frequency and IL-17A levels at various time points postinfection. In addition, Th17 cells were the predominant sources of IL-17A in PBMCs of patients infected with H7N9 virus. Taken together, our results indicate immune disorder in acute H7N9 infection and a restored Th17 and Tc17 cell frequency might serve as a biomarker for predicting recovery in patients infected with this virus.


Assuntos
Linfócitos T CD8-Positivos/citologia , Influenza Humana/imunologia , Interleucina-17/sangue , Células Th17/citologia , Doença Aguda , Adulto , Idoso , Animais , Células Cultivadas , Feminino , Humanos , Subtipo H7N9 do Vírus da Influenza A , Masculino , Pessoa de Meia-Idade , Aves Domésticas/virologia
8.
J Immunol Res ; 2019: 8505021, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049361

RESUMO

Objective: This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods: 133 patients diagnosed with primary invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results: The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, p < 0.05). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, p < 0.05). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (p < 0.05), respectively. Conclusion: The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/citologia , Carcinoma Ductal de Mama/patologia , Linfócitos do Interstício Tumoral/citologia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral , Idoso , Grupo com Ancestrais do Continente Asiático , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Contagem de Células , China , Estudos Transversais , Feminino , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Ann Lab Med ; 39(5): 430-437, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31037861

RESUMO

BACKGROUND: T cell immunophenotypes in patients with hemophagocytic lymphohistiocytosis (HLH) have been described. Downregulation of CD5 or CD7 on T cells has been reported in patients with Epstein-Barr virus (EBV)-positive HLH. As the utility of T cell immunophenotypes as an adjunctive diagnostic or a prognostic marker for HLH has not been evaluated, we analyzed T cell immunophenotypes in HLH patients for this purpose. METHODS: We classified 45 HLH patients into three subgroups: EBV-positive HLH (N=27), EBV-negative secondary HLH (N=15), and familial HLH (N=3). We retrospectively characterized downregulation patterns of CD5 or CD7 on activated T cells, using flow cytometry. Overall survival was estimated using Kaplan-Meier curves and compared using the log-rank test. RESULTS: An aberrant immunophenotype, including CD5 and/or CD7 downregulation on T cells, was observed in 55.6% (15/27) of the EBV-positive HLH patients and 100% of the familial HLH (3/3). Only one (1/15, 6.7%) patient with EBV-negative secondary HLH showed an aberrant loss of CD7 antigen on CD8+ T cells. The presence of an aberrant T cell immunophenotype was not related to overall survival in EBV-positive HLH and EBV-negative secondary HLH patients. CONCLUSIONS: An aberrant T cell immunophenotype may assist in discriminating EBV-negative secondary HLH and EBV-positive HLH. However, it may not be useful as a prognostic marker.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Linfo-Histiocitose Hemofagocítica/diagnóstico , Adolescente , Adulto , Idoso , Antígenos CD7/metabolismo , Antígenos CD5/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunofenotipagem , Lactente , Estimativa de Kaplan-Meier , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
EBioMedicine ; 42: 109-119, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30956171

RESUMO

BACKGROUND: HIV-1-specific CD8+ T cells are required for immune suppression of HIV-1 replication and elimination of the associated viral reservoirs. However, effective induction of functional HIV-1-specific CD8+ T cells from naïve cells remains problematic in the setting of human vaccine trials. In this study, we investigated priming of functional HIV-1-specific CD8+ T cells from naïve cells. METHODS: HIV-1-specific CD8+ T cells were primed from naïve T cells of HIV-1-seronegative individuals using TLR4 ligand LPS or STING ligand 3'3'-cGAMP in vitro. We established HIV-1-specific CD8+ T cell lines from primed T cells and then investigated functional properties of these cells. FINDINGS: HIV-1-specific CD8+ T cells primed with LPS failed to suppress HIV-1. In contrast, 3'3'-cGAMP effectively primed HIV-1-specific CD8+ T cells with strong ability to suppress HIV-1. 3'3'-cGAMP-primed T cells had higher expression levels of perforin and granzyme B than LPS-primed ones. The expression levels of granzyme B and perforin and viral suppression ability of 3'3'-cGAMP-primed T cells were positively correlated with the production level of type I IFN from PBMCs stimulated with 3'3'-cGAMP. INTERPRETATION: The present study demonstrates the potential of 3'3'-cGAMP to induce HIV-1-specific CD8+ T cells with strong effector function from naïve cells via a strong type I IFN production and suggests that this STING ligand may be useful for AIDS vaccine and cure treatment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Subpopulações de Linfócitos T/imunologia , Biomarcadores , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Carga Viral , Replicação Viral
11.
Adv Mater ; 31(23): e1807359, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968468

RESUMO

T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation-termed an artificial T-cell stimulating matrix (aTM). It is found that biophysical properties of the aTM-stimulatory ligand density, stiffness, and ECM proteins-potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.


Assuntos
Células Artificiais/citologia , Engenharia Celular/métodos , Imunoterapia/métodos , Linfócitos T/citologia , Transferência Adotiva , Animais , Células Artificiais/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Matriz Extracelular/química , Humanos , Ácido Hialurônico/química , Hidrogéis , Ligantes , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
Acta Haematol ; 141(3): 189-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840964

RESUMO

Calorie restriction (CR) has been studied as a way to prolong longevity, and CR before chemotherapy can reduce hematological toxicity in cancer patients. We investigated the influence of fasting on immune cells and immature hematopoietic cells. In fasted mice, there was a significant reduction in the hematopoietic stem cell count but no significant difference for progenitor cells. Colony assays showed no difference and the rates of early and late apoptosis were almost identical when comparing fasted and control mice. DNA cell cycle analysis of immature bone marrow (BM) cells showed that CR caused a significant increase in the percentage in the G0/G1 phase and decreases in the S and G2/M phases. We detected a remarkable increase of T cells in the BM of fasted mice. CD44- naïve CD8+ T cells were more numerous in fasted BM, as were naïve CD4+ T cells, and part of those T cells showed less tendency in the G0/G1 phase. Immature hematopoietic cells remained in a relatively quiescent state and retention of colony-forming capacity during CR. The number of naïve T cells in the BM of fasted mice increased. These findings imply immature hematopoietic cells and some lymphoid cells can survive starvation, whilst maintaining their function.


Assuntos
Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Jejum/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Células-Tronco Hematopoéticas/citologia , Camundongos
13.
BMC Infect Dis ; 19(1): 216, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832595

RESUMO

BACKGROUND: Hepatitis B virus (HBV) replicates non-cytopathically in the hepatocytes and HBV-related diseases are caused by immune-mediated inflammatory events. This study aimed to identify the relationship between clinical-virological characteristics and immunity in untreated chronic hepatitis B (CHB) patients. METHODS: A total of 209 CHB patients were categorized into immune tolerant (IT, n = 17), inactive carrier (IC, n = 20), immune active (IA, n = 120), and gray zone (GZ, n = 72) phases. The quantitative hepatitis B surface antigen (qHBsAg), hepatitis B e antigen (HBeAg), anti-HBeAg (HBeAb), HBV genotype, viral mutant and frequencies of interleukin (IL)-4, IL-17, IL-10 and interferon-gamma (IFN-γ) produced by CD4+ and CD8+ T cells were tested. We also correlated these cytokines with clinical-virological characteristics using a linear regression model. RESULTS: CD8+ T cells frequency were significantly decreased in IT patients. Levels of CD4+ T cells IL-4+ or IL-10+ were strongly negatively associated with qHBsAg titers. The frequency of IFN-γ produced by CD4+ and CD8+ T cells showed significant positive association with age and alanine aminotransferase (ALT) level, while that had negative association with qHBsAg titers. Additionally, the ratios of mutations in the HBV precore (PC) stop codon and basal core promoter (BCP) and the combined mutations were 32.5, 27.2, and 11.3%, respectively. The frequency of CD4+ T cells IL-17+ was higher in patients with a PC mutation than that in patients carrying a wild-type sequence. Finally, little associations among T cell derived IL-4, IL-10, IL-17, and IFN-γ was observed in the current untreated CHB cohort. CONCLUSIONS: Several components of the immune system were correlated with HBV factors that influence an inflammatory process during CHB. Of particular relevance are the significant associations of between CD4+ T cells IL-4+ and qHBsAg level, and between CD4+ T cells IL-17+ and the presence of a mutation in PC.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Hepatite B Crônica/patologia , Adulto , Fatores Etários , Alanina Transaminase/sangue , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , DNA Viral/genética , DNA Viral/metabolismo , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade
14.
Scand J Immunol ; 89(6): e12765, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30921475

RESUMO

CD137 is a promising target for immunostimulation strategies against cancer. Previous studies showed that CD137+ CD8+ T cells are enriched in antitumour effector T cells in both preclinical tumour models and cancer patients, but to date, such T cells in the blood of lung cancer patients have not been sufficiently investigated. In this study, circulating antigen-activated CD8+ T cell subsets, identified as CD137+ CD8+ or PD-1+ (programmed cell death protein 1) CD8+ , and regulatory T cells (Treg), identified as CD4+ CD25+ CD127low/- , in 40 untreated lung cancer patients and in 49 age- and sex-matched healthy controls (HCs) were assessed by flow cytometry. Results were evaluated for associations with lung cancer patient clinical characteristics. Correlations between antigen-activated CD8+ T cells and effector Treg (CTLA-4+ [cytotoxic T-lymphocyte antigen 4] CD4+ CD25+ CD127low/- ) were also investigated. Higher percentages of PD-1+ , CD137+ and PD-1+ CD137+ amongst CD8+ T cells were observed in lung cancer patients compared with HCs. The percentages of CD137+ CD8+ and PD-1+ CD137+ CD8+ T cell subsets amongst CD8+ T cells were positively correlated with thoracic tumour burden and were strongly positively correlated with the percentage of effector Treg subset. Smoking patients harboured higher percentages of the PD-1+ CD8+ T cell subset compared with non-smoking patients. This study demonstrated that circulating antigen-activated CD8+ T cells accumulated in lung cancer patients along with increased effector Treg and thoracic tumour burden. These findings aid a better understanding of immune-host interactions in lung cancer patients using peripheral blood, and further support immunotherapeutic intervention strategies using combination therapy for differential control of Treg and activation of tumour-specific effector T cells.


Assuntos
Ligante 4-1BB/metabolismo , Linfócitos T CD8-Positivos/citologia , Neoplasias Pulmonares/patologia , Linfócitos T Reguladores/citologia , Carga Tumoral/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia
15.
EBioMedicine ; 41: 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827931

RESUMO

PURPOSE: Radiation-induced sarcoma (RIS) is a rare but serious event. Its occurrence has been discussed during the implementation of new radiation techniques and justified appropriate radioprotection requirements. New approaches targeting intrinsic radio-sensitivity have been described, such as radiation-induced CD8 T-lymphocyte apoptosis (RILA) able to predict late radio-induced toxicities. We studied the role of RILA as a predisposing factor for RIS as a late adverse event following radiation therapy (RT). PATIENTS AND METHODS: In this prospective biological study, a total of 120 patients diagnosed with RIS were matched with 240 control patients with cancer other than sarcoma, for age, sex, primary tumor location and delay after radiation. RILA was prospectively assessed from blood samples using flow cytometry. RESULTS: Three hundred and forty-seven patients were analyzed (118 RIS patients and 229 matched control patients). A majority (74%) were initially treated by RT for breast cancer. The mean RT dose was comparable with a similar mean (± standard deviation) for RIS (53.7 ±â€¯16.0 Gy) and control patients (57.1 ±â€¯15.1 Gy) (p = .053). Median RILA values were significantly lower in RIS than in control patients with respectively 18.5% [5.5-55.7] and 22.3% [3.8-52.2] (p = .0008). Thus, patients with a RILA >21.3% are less likely to develop RIS (p < .0001, OR: 0.358, 95%CI [0.221-0.599]. CONCLUSION: RILA is a promising indicator to predict an individual risk of developing RIS. Our results should be followed up and compared with molecular and genomic testing in order to better identify patients at risk. A dedicated strategy could be developed to define and inform high-risk patients who require a specific approach for primary tumor treatment and long term follow-up.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Induzidas por Radiação/patologia , Sarcoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Área Sob a Curva , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/imunologia , Estudos Prospectivos , Curva ROC , Sarcoma/imunologia , Adulto Jovem
16.
ACS Appl Mater Interfaces ; 11(15): 13964-13972, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30912920

RESUMO

Nanomaterial-based tumor photothermal therapy (PTT) has attracted increasing attention and been a promising method for cancer treatment because of its low level of adverse effects and noninvasiveness. However, thermotherapy alone still cannot control tumor metastasis and recurrence. Here, we developed surface-functionalized modified copper sulfide nanoparticles (CuS NPs). CuS NPs can not only be used as photothermal mediators for tumor hyperthermia but can adsorb tumor antigens released during hyperthermia as an antigen-capturing agent to induce antitumor immune response. We selected maleimide polyethylene glycol-modified CuS NPs (CuS NPs-PEG-Mal) with stronger antigen adsorption capacity, in combination with an immune checkpoint blocker (anti-PD-L1) to evaluate the effect of hyperthermia, improving immunotherapy in a 4T1 breast cancer tumor model. The results showed that hyperthermia based on CuS NPs-PEG-Mal distinctly increased the levels of inflammatory cytokines in the serum, leading to a tumor immunogenic microenvironment. In cooperation with anti-PD-L1, PTT mediated by CuS NPs-PEG-Mal enhanced the number of tumor-infiltrating CD8+ T cells and inhibited the growth in primary and distant tumor sites of the 4T1 tumor model. The therapeutic strategies provide a simple and effective treatment option for metastatic and recurrent tumors.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/terapia , Cobre/química , Nanopartículas/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Feminino , Humanos , Hipertermia Induzida , Imunoterapia , Lasers , Maleimidas/química , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/toxicidade , Fototerapia , Polietilenoglicóis/química
17.
Nat Methods ; 16(2): 191-198, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700902

RESUMO

CD8+ T cells recognize and eliminate tumors in an antigen-specific manner. Despite progress in characterizing the antitumor T cell repertoire and function, the identification of target antigens remains a challenge. Here we describe the use of chimeric receptors called signaling and antigen-presenting bifunctional receptors (SABRs) in a cell-based platform for T cell receptor (TCR) antigen discovery. SABRs present an extracellular complex comprising a peptide and major histocompatibility complex (MHC), and induce intracellular signaling via a TCR-like signal after binding with a cognate TCR. We devised a strategy for antigen discovery using SABR libraries to screen thousands of antigenic epitopes. We validated this platform by identifying the targets recognized by public TCRs of known specificities. Moreover, we extended this approach for personalized neoantigen discovery.


Assuntos
Apresentação do Antígeno , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Apresentadoras de Antígenos/citologia , Antígenos/química , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/citologia , Clonagem Molecular , Técnicas de Cocultura , Epitopos/química , Reações Falso-Positivas , Biblioteca Gênica , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Imunoterapia/métodos , Células Jurkat , Células K562 , Lectinas Tipo C/metabolismo , Complexo Principal de Histocompatibilidade , Oligonucleotídeos/genética , Peptídeos/química
18.
Mediators Inflamm ; 2019: 3231696, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30733641

RESUMO

The bone marrow (BM) is not only a reservoir of hematopoietic stem cells but a repository of immunological memory cells. Further characterizing BM-resident memory T cells would be helpful to reveal the complicated relationship between the BM and immunological memory. In this study, we identified CD122high stem cell antigen-1 (Sca-1) high B cell lymphoma 2 (Bcl-2) high CD4+ stem cell-like memory T cells (TSCMs) as a distinct memory T cell subset, which preferentially reside in the BM, where they respond vigorously to blood-borne antigens. Interestingly, the natural CD4+ TSCMs homing to the BM colocalized with VCAM-1+ IL-15+ IL-7+ CXCL-12+ stromal cells. Furthermore, compared to spleen-resident CD4+ TSCMs, BM-resident TSCMs induced the production of high-affinity antibodies against influenza by B lymphocytes more efficiently. Taken together, these observations indicate that the BM provides an appropriate microenvironment for the survival of CD4+ TSCMs, which broadens our knowledge regarding the memory maintenance of antigen-specific CD4+ T lymphocytes.


Assuntos
Anticorpos Antivirais/imunologia , Células da Medula Óssea/citologia , Linfócitos T CD4-Positivos/citologia , Memória Imunológica , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/terapia , Animais , Ataxina-1/metabolismo , Linfócitos T CD8-Positivos/citologia , Quimiocina CXCL12/metabolismo , Células-Tronco Hematopoéticas/citologia , Interleucina-15/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Estromais , Molécula 1 de Adesão de Célula Vascular/metabolismo
19.
Biomater Sci ; 7(5): 1875-1887, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30789175

RESUMO

We describe the synthesis of CpG oligodeoxynucleotide-coated Prussian blue nanoparticles (CpG-PBNPs) that function as a nanoimmunotherapy for neuroblastoma, a common childhood cancer. These CpG-PBNPs increase the antigenicity and adjuvanticity of the treated tumors, ultimately driving robust antitumor immunity through a multi-pronged mechanism. CpG-PBNPs are synthesized using a facile layer-by-layer coating scheme resulting in nanoparticles that exhibit monodisperse size distributions and multiday stability without cytotoxicity. The strong intrinsic absorption of PBNPs in the CpG-PBNPs enables ablative photothermal therapy (CpG-PBNP-PTT) that triggers tumor cell death, as well as the release of tumor antigens to increase antigenicity. Simultaneously, the CpG coating functions as an exogenous molecular adjuvant that complements the endogenous adjuvants released by the CpG-PBNP-PTT (e.g. ATP, calreticulin, and HMGB1). In cell culture, coating NPs with CpG increases immunogenicity while maintaining the photothermal activity of PBNPs. When administered in a syngeneic, Neuro2a-based, murine model of neuroblastoma, CpG-PBNP-PTT results in complete tumor regression in a significantly higher proportion (70% at 60 days) of treated animals relative to controls. Furthermore, the long-term surviving, CpG-PBNP-PTT-treated animals reject Neuro2a rechallenge, suggesting that this therapy generates immunological memory. Our findings point to the importance of simultaneous cytotoxicity, antigenicity, and adjuvanticity to generate robust and persistent antitumor immune responses against neuroblastoma.


Assuntos
Ferrocianetos/química , Ferrocianetos/imunologia , Nanopartículas/química , Neuroblastoma/patologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Concentração de Íons de Hidrogênio , Camundongos , Neuroblastoma/imunologia , Oligodesoxirribonucleotídeos/química , Fototerapia
20.
Exerc Immunol Rev ; 25: 64-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30753130

RESUMO

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Beta cell specific T cells are highly differentiated and show evidence of previous antigen exposure. Exerciseinduced mobilisation of highly-differentiated CD8+ T cells facilitates immune surveillance and regulation. We aimed to explore exercise-induced T cell mobilisation in T1D. In this study, we compared the effects of a single bout of vigorous intensity exercise on T cell mobilisation in T1D and control participants. N=12 T1D (mean age 33.2yrs, predicted VO2 max 32.2 mL/(kg·min), BMI 25.3Kg/m2) and N=12 control (mean age 29.4yrs, predicted VO2 max 38.5mL(kg.min), BMI 23.7Kg/m2) male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. Exercise-induced mobilisation was observed for T cells in both T1D and control groups. Total CD8+ T cells mobilised to a similar extent in T1D (42.7%; p=0.016) and controls (39.7%; p=0.001). CD8 effector memory CD45RA+ (EMRA) subset were the only T cell lineage subset to be significantly mobilised in both groups though the percentage increase of CD8+ EMRA was blunted in T1D (T1D (26.5%) p=0.004, control (66.1%) p=0.010). Further phenotyping of these subsets revealed that the blunting was most evident in CD8+ EMRA that expressed adhesion (CD11b: T1D 37.70%, Control 91.48%) and activation markers (CD69: T1D 29.87%, Control 161.43%), and appeared to be the most differentiated (CD27-CD28-: T1D 7.12%, Control 113.76%). CD4+ T cells mobilised during vigorous intensity exercise in controls (p=0.001), but not in T1D. The blunted mobilisation response of particular T cell subsets was not due to CMV serostatus or apparent differences in exertion during the exercise bout as defined by heart rate and RPE. Predicted VO2 max showed a trend to be lower in the T1D group than the control group but is unlikely to contribute to this blunted response. We postulate the reasons for a blunted mobilisation of differentiated CD8+ EMRA cells includes differences in blood glucose, adrenaline receptor density, and sequestration of T cells in the pancreas of T1D participants. In conclusion, mobilisation of CD8+ EMRA and CD4+ subsets T cells is decreased in people with T1D during acute exercise.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diabetes Mellitus Tipo 1/imunologia , Exercício , Adulto , Linfócitos T CD4-Positivos/citologia , Humanos , Masculino
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