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1.
Annu Rev Immunol ; 38: 229-247, 2020 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31928469

RESUMO

Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.


Assuntos
Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Biomarcadores , Diferenciação Celular/imunologia , Interações Hospedeiro-Patógeno , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/imunologia , Células Progenitoras Linfoides/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/citologia
2.
Adv Exp Med Biol ; 1409: 193-203, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36038808

RESUMO

Heat shock proteins (HSPs) are a group of proteins that promote protein folding, inhibit denaturation of cellular proteins, and maintain other proteins' functional activities when cells are subjected to stress and/or high temperature. HSP classification is generally based on their molecular weights into large and small HSP. The family of small HSPs includes HSPs 27, 40, 60, 70, and 90. The potential roles of HSP27 and HSP70 are quite evident in different solid malignancies, including breast, colorectal, pancreatic, and liver cancers. In this chapter, the authors focus on HSP27 and HSP70 signaling in oncology and their role in different solid malignancies as well as they shed light on the novel role of HSP70 and HSP90 in the immune-oncology field.


Assuntos
Proteínas de Choque Térmico HSP27 , Neoplasias Hepáticas , Humanos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo
3.
Microsc Microanal ; 29(3): 1228-1243, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37749682

RESUMO

The prognosis of metastatic lung melanoma (MLM) has been reported to be poor. An increasing number of studies have reported the function of several immune cells in cancer regression. Although the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of inflammatory lung lesions has been previously reported, the association between MLM progression and MFALCs development has remained unexplored. Herein, we compared the microenvironmental changes in the lungs and MFALCs among phosphate-buffered saline (PBS) and cancer groups at early (1 week) and late (2 weeks) stages following the intravenous injection of B16-F10 melanoma cells into C57BL/6 mice. Except for lung CD4+ helper T-cells and Iba1+ macrophage populations of early stage, we observed a significant increase in the proliferating and immune cell (CD20+ B-lymphocytes, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, CD16+ natural killer (NK) cells populations, area of high endothelial venules, and lung lymphatic vessels in cancer groups at both the stages as compared with the PBS groups. Furthermore, a significant positive correlation was observed between immune cell populations in MFALCs and the lungs (B- and T-lymphocytes, and NK cells in both stages). Collectively, our findings suggest a promising cancer therapeutic strategy via targeting immune cells in MFALCs.


Assuntos
Neoplasias Pulmonares , Melanoma , Camundongos , Animais , Camundongos Endogâmicos C57BL , Mediastino , Pulmão
4.
Adv Exp Med Biol ; 1290: 51-65, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33559854

RESUMO

Unlike other malignancies, ovarian cancer (OC) creates a complex tumor microenvironment with distinctive peritoneal ascites consisting of a mixture of several immunosuppressive cells which impair the ability of the patient's immune system to fight the disease. The poor survival rates observed in advanced stage OC patients and the lack of effective conventional therapeutic options have been attributed in large part to the immature dendritic cells (DCs), IL-10 secreting regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer stem cells that secrete inhibitory cytokines. This review highlights the critical role played by the intraperitoneal presence of IL-10 in the generation of an immunosuppressive tumor microenvironment. Further, the effect of antibody neutralization of IL-10 on the efficacy of DC and chimeric antigen receptor T-cell vaccines will be discussed. Moreover, we will review the influence of IL-10 in the promotion of cancer stemness in concert with the NF-κB signaling pathway with regard to OC progression. Finally, understanding the role of IL-10 and its crosstalk with various cells in the ascitic fluid may contribute to the development of novel immunotherapeutic approaches with the potential to kill drug-resistant OC cells while minimizing toxic side effects.


Assuntos
Interleucina-10 , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Células Dendríticas , Feminino , Humanos , Neoplasias Ovarianas/terapia , Transdução de Sinais , Microambiente Tumoral
5.
Int J Mol Sci ; 22(20)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34681595

RESUMO

We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vß2 CD8+ cytotoxic T cells and CD16 + CD56- NK cells. This is the first presentation of TCR-specific T cell oligoclonal response in COVID-19. Our study suggests that B-cell depleted patients may effectively respond to anti-SARS-CoV-2 treatment when NK and antigen-specific Tc cell response is induced.


Assuntos
COVID-19/terapia , Células Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/metabolismo , COVID-19/virologia , Humanos , Imunização Passiva , SARS-CoV-2/isolamento & purificação , Soroterapia para COVID-19
6.
Am J Respir Crit Care Med ; 199(4): 465-477, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30371106

RESUMO

BACKGROUND: Type 2 (T2) inflammation drives airway dysfunction in many patients with asthma; yet, we lack a comprehensive understanding of the airway immune cell types and networks that sustain this inflammation. Moreover, defects in the airway immune system in patients with asthma without T2 inflammation are not established. OBJECTIVES: To determine the gene networks that sustain T2 airway inflammation in T2-high asthma and to explore the gene networks that characterize T2-low asthma. METHODS: Network analysis of sputum cell transcriptome expression data from 84 subjects with asthma and 27 healthy control subjects was used to identify immune cell type-enriched networks that underlie asthma subgroups. RESULTS: Sputum T2 gene expression was characterized by an immune cell network derived from multiple innate immune cells, including eosinophils, mast cells/basophils, and inflammatory dendritic cells. Clustering of subjects within this network stratified subjects into T2-high and T2-low groups, but it also revealed a subgroup of T2-high subjects with uniformly higher expression of the T2 network. These "T2-ultrahigh subjects" were characterized clinically by older age and more severe airflow obstruction and pathologically by a second T2 network derived from T2-skewed, CD11b+/CD103-/IRF4+ classical dendritic cells. Subjects with T2-low asthma were differentiated from healthy control subjects by lower expression of a cytotoxic CD8+ T-cell network, which was negatively correlated with body mass index and plasma IL-6 concentrations. CONCLUSIONS: Persistent airway T2 inflammation is a complex construct of innate and adaptive immunity gene expression networks that are variable across individuals with asthma and persist despite steroid treatment. Individuals with T2-low asthma exhibit an airway deficiency in cytotoxic T cells associated with obesity-driven inflammation.


Assuntos
Asma/imunologia , Perfilação da Expressão Gênica/métodos , Adulto , Asma/complicações , Asma/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/imunologia , Obesidade/metabolismo , Escarro/imunologia
7.
Eur J Immunol ; 47(5): 872-879, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28295265

RESUMO

Activation of the C-type lectin receptor Dectin-1 by ß-glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8+ cytotoxic T-cell (CTL) responses without additional adjuvants, the Dectin-1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin-1-induced CTL cross-priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice. Thus, our results demonstrate that Dectin-1-triggered Card9 signaling but not inflammasome activation can potently cross-prime Ag-specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Lectinas Tipo C/metabolismo , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Apresentação Cruzada , Imunidade Inata , Inflamassomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/fisiopatologia , Transdução de Sinais , Vacinação
8.
Vet Immunol Immunopathol ; 275: 110814, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39142123

RESUMO

Analysis of the recall response ex vivo in cattle vaccinated with a Mycobacterium avium subsp. paratuberculosis (Map) rel deletion mutant revealed the immune response was directed toward a 35 kD major membrane protein (MMP) of Map. Antigen presenting cells (APC) primed with MMP elicited expansion of CD8 cytotoxic memory T cells (CTL) with ability to kill intracellular bacteria. Development of CTL was MHC-restricted. The gene MAP2121c, encoding MMP, was modified for expression of MMP (tPA-MMP-2mut) in a mammalian cell line to explore the potential of developing MMP as a vaccine. Ex vivo stimulation of PBMC, from Map free cattle, with APC primed with tPA-MMP-2mut expressed p35 elicited a primary CD8 CTL response comparable to the recall response elicited with PBMC from cattle vaccinated with either the Maprel deletion mutant or MMP. In the present study, the modified gene for MMP, now referred to as p35NN, was placed into a bovine herpes virus-4 (BoHV4) vector to determine the potential use of BoHV-4AΔTK-p35NN as a peptide-based vaccine. Subcutaneous vaccination of healthy cattle with BoHV-4AΔTK-p35NN elicited a CTL recall response, as detected ex vivo. The results show use of a virus vector is an effective way for delivery of MMP as a vaccine. The immunogenic activity of MMP was not lost when modified for expression in mammalian cells. The next step is to conduct a field trial to determine if presence of an immune response to MMP prevents Map from establishing an infection.


Assuntos
Vacinas Bacterianas , Doenças dos Bovinos , Mycobacterium avium subsp. paratuberculosis , Paratuberculose , Linfócitos T Citotóxicos , Animais , Bovinos , Mycobacterium avium subsp. paratuberculosis/imunologia , Paratuberculose/imunologia , Paratuberculose/prevenção & controle , Vacinas Bacterianas/imunologia , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/prevenção & controle , Doenças dos Bovinos/microbiologia , Linfócitos T Citotóxicos/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/genética , Vacinação/veterinária , Vetores Genéticos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética
9.
Adv Sci (Weinh) ; 11(18): e2310065, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38447147

RESUMO

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell-mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA-mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA-ERK1/2-ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA-treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Linfócitos T CD8-Positivos , Cumarínicos , Animais , Humanos , Camundongos , Autofagia/imunologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo
10.
Biochim Biophys Acta Rev Cancer ; 1879(5): 189161, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-39096977

RESUMO

Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8+ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.


Assuntos
Endossomos , Antígenos de Histocompatibilidade Classe I , Imunoterapia , Lisossomos , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Lisossomos/metabolismo , Endossomos/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoterapia/métodos , Animais , Transporte Proteico , Microambiente Tumoral/imunologia , Apresentação de Antígeno/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia
11.
Expert Rev Clin Immunol ; 20(7): 695-702, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38879876

RESUMO

INTRODUCTION: Vitiligo is a chronic, autoimmune condition characterized by skin depigmentation caused by inflammatory-mediated melanocyte degradation. Treatment of vitiligo is challenging due to the chronic nature of the condition. Ruxolitinib cream 1.5% was recently approved by the Food and Drug Administration (FDA) as a Janus kinase 1 and 2 inhibitor for use in nonsegmental vitiligo for those 12 years and older. AREAS COVERED: The purpose of this review is to describe the role of ruxolitinib in treating nonsegmental vitiligo.We searched PubMed using search terms nonsegmental vitiligo, jak inhibitor, and ruxolitinib. Clinicaltrials.gov was used to identify clinical trial data including efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability. EXPERT OPINION: In both phase II and phase III (TRuE-V1 and TRuE-V2) trials, ruxolitinib cream 1.5% improved repigmentation with minimal adverse effects. Topical ruxolitinib is a much needed new vitiligo treatment option.  Real life efficacy may not match that seen in clinical trials if the hurdle of poor adherence to topical treatment is not surmounted.


Assuntos
Nitrilas , Pirazóis , Pirimidinas , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Janus Quinase 1/antagonistas & inibidores , Creme para a Pele/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico
12.
J Exp Clin Cancer Res ; 42(1): 22, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36639681

RESUMO

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice. METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing. RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell. CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.


Assuntos
Linfócitos T CD8-Positivos , Carcinoma , Animais , Camundongos , Óxido Nítrico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Reposicionamento de Medicamentos , Camundongos Endogâmicos C57BL , Camundongos SCID , Citocinas , Microambiente Tumoral
13.
Cancer Lett ; 558: 216095, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36796670

RESUMO

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linfócitos T Citotóxicos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Linfócitos T CD8-Positivos , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Imunidade , Microambiente Tumoral , Fosfolipases A2 do Grupo II , Neoplasias Pancreáticas
14.
Clin Transl Oncol ; 24(10): 2029-2038, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35731350

RESUMO

PURPOSE: OX40 signaling pathway occupies a vital place in anti-tumor immunity; however, the role of tumor-infiltrating OX40+ lymphocytes in pancreatic ductal adenocarcinoma (PDAC) remains to be identified. METHODS: A total of 325 sequential PDAC patients who received curative tumor resection between January 2014 and December 2016 were enrolled. Tissues of these patients were immunohistochemically assessed for tumor infiltration of CD4+ T cells, CD8+ cytotoxic T cells (CTLs), and OX40+ lymphocytes. The frequency of OX40+ tumor-infiltrating lymphocytes (TILs) was then analyzed to various clinicopathological features, densities of tumor infiltration of CD4+ T cells and CTLs, and survival analysis was conducted using Kaplan-Meier (KM) curves. The risk scores of associated markers were calculated by the Cox proportional-hazards model. RESULTS: Our results showed that higher OX40+ lymphocytes infiltration was significantly correlated with superior median overall survival (OS) (25.8 vs 13.4 months, P < 0.001). Additionally, using univariate and multivariate Cox proportional hazards analyses, this study revealed that together with tumor differentiation, tumor size, serum CA199 levels, serum CA125 levels, and the infiltration of intratumoral CD8+ T cells. The abundance of OX40+ lymphocytes within the tumor was continued to be an independent predictor for OS (P = 0.023, HR = 0.713, 95% CI: 0.532-0.954). CONCLUSIONS: This study demonstrated that intratumoral infiltration by a high number of OX40+ lymphocytes is a novel biomarker for favorable prognosis in resected PDAC patients, which implies that OX40-agonist-based immunotherapy might be a potential target in PDAC patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Linfócitos T CD8-Positivos , Humanos , Linfócitos do Interstício Tumoral , Prognóstico , Neoplasias Pancreáticas
15.
Front Immunol ; 13: 1081889, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36703979

RESUMO

Peripheral blood immune cells have different molecular characteristics at different stages of the whole lifespan. Knowledge of circulating immune cell types and states from children to centenarians remains incomplete. We profiled peripheral blood mononuclear cells (PBMCs) of multiple age groups with single-cell RNA sequencing (scRNA-seq), involving the age ranges of 1-12 (G1), 20-30(G2), 30-60(G3), 60-80(G4), and >110 years (G5). The proportion and states of myeloid cells change significantly from G1 to G2. We identified a novel CD8+CCR7+GZMB+ cytotoxic T cell subtype specific in G1, expressing naive and cytotoxic genes, and validated by flow cytometry. CD8+ T cells showed significant changes in the early stage (G1 to G2), while CD4+ T cells changed in the late stage (G4 to G5). Moreover, the intercellular crosstalk among PBMCs in G1 is very dynamic. Susceptibility genes for a variety of autoimmune diseases (AIDs) have different cell-specific expression localization, and the expression of susceptibility genes for AIDs changes with age. Notably, the CD3+ undefined T cells clearly expressed susceptibility genes for multiple AIDs, especially in G3. ETS1 and FLI1, susceptibility genes associated with systemic lupus erythematosus, were differentially expressed in CD4+ and CD8+ effector cells in G1 and G3. These results provided a valuable basis for future research on the unique immune system of the whole lifespan and AIDs.


Assuntos
Antineoplásicos , Doenças Autoimunes , Humanos , Adulto , Criança , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Leucócitos Mononucleares , Centenários , Doenças Autoimunes/metabolismo , Análise de Sequência de RNA
16.
Saudi J Biol Sci ; 29(4): 1981-1997, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34924802

RESUMO

The emergence of coronavirus disease 2019 (COVID-19) pandemic in Wuhan city, China at the end of 2019 made it urgent to identify the origin of the causal pathogen and its molecular evolution, to appropriately design an effective vaccine. This study analyzes the evolutionary background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS-2) in accordance with its close relative SARS-CoV (SARS-1), which was emerged in 2002. A comparative genomic and proteomic study was conducted on SARS-2, SARS-1, and Middle East respiratory syndrome coronavirus (MERS), which was emerged in 2012. In silico analysis inferred the genetic variability among the tested viruses. The SARS-1 genome harbored 11 genes encoding 12 proteins, while SARS-2 genome contained only 10 genes encoding for 10 proteins. MERS genome contained 11 genes encoding 11 proteins. The analysis also revealed a slight variation in the whole genome size of SARS-2 comparing to its siblings resulting from sequential insertions and deletions (indels) throughout the viral genome particularly ORF1AB, spike, ORF10 and ORF8. The effective indels were observed in the gene encoding the spike protein that is responsible for viral attachment to the angiotensin-converting enzyme 2 (ACE2) cell receptor and initiating infection. These indels are responsible for the newly emerging COVID-19 variants αCoV, ßCoV, γCoV and δCoV. Nowadays, few effective COVID-19 vaccines developed based on spike (S) glycoprotein were approved and become available worldwide. Currently available vaccines can relatively prevent the spread of COVID-19 and suppress the disease. The traditional (killed or attenuated virus vaccine and antibody-based vaccine) and innovated vaccine production technologies (RNA- and DNA-based vaccines and viral vectors) are summarized in this review. We finally highlight the most common questions related to COVID-19 disease and the benefits of getting vaccinated.

17.
Vaccines (Basel) ; 9(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34696193

RESUMO

Lack of understanding of the immune response to mycobacterial pathogens has impeded progress in development of vaccines. Infection leads to development of an immune response that controls infection but is unable to eliminate the pathogen, resulting in a persistent infection. Although this puzzle remains to be solved, progress has been made using cattle as a model species to study the immune response to a prototypic mycobacterium, Mycobacterium a. paratuberculosis (Map). As chronicled in the review, incremental advances in characterizing the immune response to mycobacteria during the last 30 years with increases in information on the evolution of mycobacteria and relA, a gene regulating the stringent response, have brought us closer to an answer. We provide a brief overview of how mycobacterial pathogens were introduced into cattle during the transition of humankind to nomadic pastoralists who domesticated animals for food and farming. We summarize what is known about speciation of mycobacteria since the discovery of Mybacterium tuberculsis Mtb, M. bovis Mbv, and Map as zoonotic pathogens and discuss the challenges inherent in the development of vaccines to mycobacteria. We then describe how cattle were used to characterize the immune response to a prototypic mycobacterial pathogen and development of novel candidate vaccines.

18.
Aging (Albany NY) ; 13(11): 14590-14603, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083496

RESUMO

CD8+ cytotoxic T-lymphocytes are essential components of the anti-tumor immunity. To better understand the expansion of CD8+ T-cells we used multiplex fluorescence immunohistochemistry to study Ki67+CD8+ cells in normal lymphoid tissues, selected inflammatory diseases and cancers in 41 large sections/ microenvironment tissue microarrays (TMAs) as well as 765 samples in a conventional TMA format. The evaluation of more than 20 different compartments of normal lymphoid tissues revealed that the percentage of proliferating (ki67+) CD8+ cells did commonly not exceed 3%. In inflammations, the percentage of Ki67+CD8+ cells was more variable and higher compared to normal tissues. In cancers, the percentage of Ki67+CD8+ cells was higher in the tumor center than at the invasive margin. In the tumor center of 765 colorectal cancers, the density of Ki67+CD8+ cells and the percentage of proliferating CD8+ cytotoxic T-cells was significantly associated with microsatellite instability (p<0.0001), pT (p<0.0002) and pN category (p<0.0098). In summary, these data show that the percentage of Ki67+CD8+ cells is usually at a baseline proliferation rate below 3% in healthy secondary lymphoid organs. This rate is often markedly higher in inflammatory and neoplastic diseases compared to normal tissues. The striking link with unfavorable tumor features in colorectal cancer suggest a potential clinical utility of assessing the percentage of Ki67+CD8+ cells to predict patients outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Antígeno Ki-67/metabolismo , Fenótipo
19.
Parasitol Int ; 81: 102259, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33271362

RESUMO

Toxoplasma gondii, an obligate intracellular protozoan parasite, can establish a chronic infection in the brain by forming tissue cysts. This chronic infection is widespread in humans worldwide including developed countries, with up to one third of the population being estimated to be infected with this parasite. Diagnosis of this chronic infection is usually conducted by serological detection of IgG antibodies against this parasite. Since infected individuals remain positive for these antibodies for years, it has generally been considered that this infection is a lifelong infection. It is also often considered that this chronic infection is "latent" or "quiescent". However, recent discovery of the capability of perforin-dependent, CD8+ T cell-mediated immune responses to eliminate T. gondii cysts in collaboration with phagocytes illustrated dynamic interplays between T. gondii cysts and host immune system during this chronic infection. Importantly, the cytotoxic T cell-mediated protective immunity is able to remove mature cysts of the parasite. It is now clear that chronic T. gondii infection is not "latent" or "quiescent". Elucidating the mechanisms of the dynamic host-pathogen interactions between the anti-cyst protective immunity and T. gondii cysts and identifying the pathway to appropriately activate anti-cyst CD8+ cytotoxic T cells would be able to open a door for eradicating T. gondii cysts and curing chronic infection with this parasite.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Toxoplasmose/imunologia , Toxoplasmose/prevenção & controle , Doença Crônica/prevenção & controle , Humanos , Toxoplasma/fisiologia
20.
Aging (Albany NY) ; 12(1): 502-517, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913856

RESUMO

Chemokines play essential roles in the progression of various human cancers; however, the expression and role of CXC chemokines in pancreatic adenocarcinoma (PAAD) have not yet been identified. The aim of this study is to identify the expression patterns, clinical significance and mechanisms of CXC chemokines in regulating tumour microenvironment of PAAD. Three CXC chemokines, including CXCL5, CXCL9, and CXCL10, were significantly overexpressed in PAAD tissues, which were correlated with the poor survival of the patients. CXCL9/10 was associated with change of immune cell pattern in the tumour microenvironment, and supplementation of CXCL9 in the orthotopic murine PAAD model promoted tumour progression. In particular, CXCL9 reduced the CD8+ cytotoxic T lymphocytes in the tumour microenvironment of PAAD, which could be attributed to the reduced CD8+ T cell proliferation, activation, and secretion of anti-tumour cytokines. In vitro treatment of CXCL9 directly led to the suppression of the proliferation, activation, and secretion of anti-tumour cytokines of isolated CD8+ T cells. Inhibition of STAT3 recovered the CXCL9-inhibited proliferation, activation, and secretion of anti-tumour cytokines of CD8+ T cells. Our study indicates CXCL9 as a potential target of immunotherapy in PAAD treatment by regulating the CD8+ T lymphocytes in the tumour microenvironment.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Quimiocina CXCL9/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Quimiocina CXCL9/genética , Quimiocina CXCL9/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Humanos , Imunomodulação , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Linfócitos T Citotóxicos/efeitos dos fármacos , Microambiente Tumoral/imunologia
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