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1.
Adv Exp Med Biol ; 1248: 1-6, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185704

RESUMO

Cancer immunotherapy, especially immune checkpoint blockade therapy, represents a hotspot in cancer research. However, the low response rate, adaptive/acquired resistance, and adverse effects still keep most cancer patients from obtaining sustained clinical benefits. To overcome these limitations, it is essential to improve our understanding on the regulation of immune checkpoints under physiological and pathological contexts. Recent researches have gained insights into the molecular control of immune checkpoint receptors and ligands, which extended our knowledge on the immune system and provided alternative strategies for developing checkpoint inhibitors.


Assuntos
Imunoterapia/tendências , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Imunoterapia/efeitos adversos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia
2.
Adv Exp Med Biol ; 1248: 201-226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185712

RESUMO

Immune checkpoint molecules, including inhibitory and stimulatory immune checkpoint molecules, are defined as ligand-receptor pairs that exert inhibitory or stimulatory effects on immune responses. Most of the immune checkpoint molecules that have been described so far are expressed on cells of the adaptive immune system, particularly on T cells, and of the innate immune system. They are crucial for maintaining the self-tolerance and modulating the length and magnitude of immune responses of effectors in different tissues to minimize the tissue damage. More and more evidences have shown that inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor types. Although the main function of tumor cell-associated immune checkpoint molecules is considered to mediate the immune evasion, it has been reported that the immune checkpoint molecules expressed on tumor cells also play important roles in the maintenance of many malignant behaviors, including self-renewal, epithelial-mesenchymal transition, metastasis, drug resistance, anti-apoptosis, angiogenesis, or enhanced energy metabolisms. In this section, we mainly focus on delineating the roles of the tumor cell-associated immune checkpoint molecules beyond immune evasion, such as PD-L1, PD-1, B7-H3, B7-H4, LILRB1, LILRB2, TIM3, CD47, CD137, and CD70.


Assuntos
Pontos de Checagem do Ciclo Celular/imunologia , Evasão da Resposta Imune , Tolerância Imunológica , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Evasão da Resposta Imune/imunologia , Tolerância Imunológica/imunologia , Linfócitos T/imunologia
3.
Adv Exp Med Biol ; 1248: 347-398, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185718

RESUMO

Checkpoint signaling involves a variety of upstream and downstream factors that participate in the regulation of checkpoint expression, activation, and degradation. During the process, phosphorylation plays a critical role. Phosphorylation is one of the most well-documented post-translational modifications of proteins. Of note, the importance of phosphorylation has been emphasized in aspects of cell activities, including proliferation, metabolism, and differentiation. Here we summarize how phosphorylation of specific molecules affects the immune activities with preference in tumor immunity. Of course, immune checkpoints are given extra attention in this book. There are many common pathways that are involved in signaling of different checkpoints. Some of them are integrated and presented as common activities in the early part of this chapter, especially those associated with PD-1/PD-L1 and CTLA-4, because investigations concerning them are particularly abundant and variant. Their distinct regulation is supplementarily discussed in their respective section. As for checkpoints that are so far not well explored, their related phosphorylation modulations are listed separately in the later part. We hope to provide a clear and systematic view of the phosphorylation-modulated immune signaling.


Assuntos
Pontos de Checagem do Ciclo Celular/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Receptores Imunológicos/imunologia , Transdução de Sinais/imunologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , Receptores Imunológicos/antagonistas & inibidores
4.
Adv Exp Med Biol ; 1248: 651-653, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185727

RESUMO

The regulation of immune checkpoint is a pivotal mechanism mediating both self-tolerance physiologically and tumor immune evasion pathologically. Along with an increasing number of identified checkpoint ligand-receptor pairs, the complexity of regulation at genetic, epigenetic, transcriptional, translational, and post-translational levels makes it highly challenging to assemble a comprehensive regulatory network. Advanced animal models are required for determining the exact regulatory effects, given the differences in human and mouse immune systems. Our further understanding on checkpoint regulation may energize translational studies aimed to improve cancer immunotherapy, and collaborations between researchers with different expertise would help to tackle existing challenges in this field.


Assuntos
Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia
5.
Adv Exp Med Biol ; 1204: 31-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32152942

RESUMO

Mincle (macrophage inducible C-type lectin, Clec4e, Clecsf9) was originally identified as a member of the C-type lectin receptor family in 1999. Then, the function of Mincle to control antifungal immunity by binding to Candida albicans was reported in 2008. Around the same time, it was reported that Mincle recognized damaged cells and induced sterile inflammation by coupling with the ITAM-adaptor molecule FcRγ. In the following year, a breakthrough discovery reported that Mincle was an essential receptor for mycobacterial cord factor (trehalose-6,6'-dimycolate, TDM). Mincle gained increasing attention immediately after this critical finding. Although our understanding of the recognition of Mycobacteria has been advanced significantly, it was also revealed that Mincle interacts with pathogens other than Mycobacteria. In addition, endogenous ligands of Mincle were identified recently. Therefore, Mincle is now considered a danger receptor both for self and non-self ligands, so-called damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). This chapter will give an overview of the accumulated knowledge of the multi-task danger receptor Mincle from its discovery to the latest findings.


Assuntos
Fatores Corda/imunologia , Lectinas Tipo C/imunologia , Mycobacterium/química , Mycobacterium/imunologia , Receptores Imunológicos/imunologia , Animais , Humanos
6.
Cancer Immunol Immunother ; 69(7): 1237-1252, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32166404

RESUMO

Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.


Assuntos
Antígenos CD/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/imunologia , Antígenos HLA-G/imunologia , Neoplasias Renais/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
7.
Medicine (Baltimore) ; 99(8): e18889, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080073

RESUMO

RATIONALE: Prostate cancer along with colorectal and lung cancers accounts for 42% of cancer cases in men globally. It is the first cancer indication for which the use of active immunotherapy, Sipuleucel-T (Provenge) was granted by the FDA in 2010. This study presents a case of prostate carcinoma and the tumour remission observed after administration of a personalised Dendritic cell vaccine (APCEDEN). PATIENT CONCERNS: A 58 years old Caucasian male diagnosed with prostate carcinoma with GLEASON score 8. The patient had previously been diagnosed with Renal Cell Carcinoma (RCC) in 1996 and had undergone nephrectomy of the right kidney. PET CT scan revealed multiple intensely PSMA avid lesions noted in both lobes of the prostate gland with SUVmax -28.3 and the prostate gland measuring 3.2 × 3.2 cm displaying maximum dimensions. DIAGNOSIS: FNAC followed by PETCT confirmed CA Prostate and further supported by increased serum PSA level. INTERVENTIONS: The patient underwent personalised Dendritic Cell Immunotherapy APCEDEN regimen of six doses biweekly, in a time frame of 3 months were given both via intravenous and intradermal route. Six months post completion of APCEDEN, the patient was administered 6 booster shots for 6 months. OUTCOMES: Progressive remission of carcinoma was observed along with reduction in PSA and Testosterone levels. PET CT showed decline in PSMA avidity by 50% with SUVmax -14.0 and normal size and shape of prostate gland. LESSONS: Prostate carcinoma is the second most common cancer in men with majority of them exhibiting locally advanced disease. Apparently 20% to 30% of them are categorized as relapsed cases after various therapeutic interventions. Modulating immune system is an emerging therapy termed as Immunotherapy and potentiates the killing cancer cells via immune activation. Interestingly, prostate cancer is slow growing and it provides the scope and time to mount an anti-tumor response which makes it an attractive target for immunotherapy. This case study demonstrates the efficacy of APCEDEN Immunotherapy regimen resulting in a significant disease remission benefiting the patient.


Assuntos
Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Carcinoma , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Lectinas Tipo C/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Nefrectomia/métodos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Receptores Imunológicos/imunologia , Indução de Remissão , Resultado do Tratamento
8.
Cancer Immunol Immunother ; 69(5): 789-797, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32055919

RESUMO

CD160 is an Ig-like glycoprotein expressed by the majority of circulating natural killer cells and γδ T cells. Whether CD160 could regulate CD8+ T-cell functions remains unknown. In this study, we investigated the effects of CD160 on CD8+ T cells in pancreatic cancer. First, we found that the frequency of PD-1+ cells was comparable between CD160+ and CD160-CD8+ T cells, with the former presenting significantly higher PD-1 expression level. In contrast, the frequency of TIM-3+ cells was higher among CD160+ cells but the expression level was comparable between CD160+ and CD160-CD8+ T cells. The IFN-γ and IL-2-expressing CD8+ T cells, directly ex vivo, were highly enriched in the CD160+ subset. However, when CD160+ and CD160-CD8+ T cells were stimulated, the proliferation levels of CD160+ and CD160- cells were initially comparable, but were significantly lower in CD160+CD8+ T cells than in CD160-CD8+ T cells later on. The IFN-γ and IL-2 transcription levels were initially higher in CD160+CD8+ T cells, but eventually reduced in CD160+CD8+ T cells compared to CD160-CD8+ T cells. Also, CD160+CD8+ T cells presented lower cytotoxic capacity than CD160-CD8+ T cells. Interestingly, we observed that tumor-infiltrating CD8+ T cells were significantly enriched with the CD160+ subset in pancreatic cancer patients. In addition, patients with higher frequencies of tumor CD160+CD8+ T cells presented lower survival. Overall, these data demonstrated that tumor-infiltrating CD8+ T cells were enriched with the CD160+ subset in pancreatic cancer, with active effector responses directly ex vivo but limited potential for further activation.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Antígenos CD/imunologia , Biópsia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Receptores Imunológicos/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/metabolismo , Fatores de Tempo
9.
Molecules ; 25(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936865

RESUMO

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.


Assuntos
Doença de Alzheimer , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Receptores Imunológicos , Regulação para Cima/imunologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Roedores
10.
Nature ; 577(7791): 549-555, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942075

RESUMO

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.


Assuntos
Linfócitos B/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Estruturas Linfoides Terciárias/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Células Clonais/citologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Dendríticas Foliculares/citologia , Células Dendríticas Foliculares/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Memória Imunológica/imunologia , Espectrometria de Massas , Melanoma/patologia , Melanoma/cirurgia , Metástase Neoplásica/genética , Fenótipo , Prognóstico , RNA-Seq , Receptores Imunológicos/imunologia , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/imunologia , Transcriptoma
11.
Mol Immunol ; 118: 99-109, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31862674

RESUMO

Immunosuppressive chemoresistance is a major barrier in lung cancer treatment. Tumor immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) play a key role in chemotherapy induced MDSC development and differentiation but their mechanistic role has not been elucidated. Here, we define a role for carboplatin based chemotherapy in potentiating an MDSC-dependent pathway that triggers the chemoresistance mechanism. Findings reveal MDSC differentiation and activation of IL-13/IL-33-mediated pathway through VCAM/RANTES following carboplatin treatment. Furthemore, secretion of T regulatory IL-10-producing CD4+Foxp3+ cells was increased followed by expression of co-inhibitory receptor TIGIT on T cells, leading to a dysfunctional T cell phenotype. These cells were characterized by an immunosuppressive phenotype with impaired activation, proliferation and cytokine production. Lung cancer tissues expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. This TIGIT expression on tumor-infiltrating T cells was found to be associated with tumor progression and was linked to functional exhaustion of T cells. In addition, the presence of plasmacytoid dendritic cells (pDCs) exposed to tumor-derived factors further enhanced tumor progression through IL-10 production and up-regulation of the inducible co-stimulatory ligand (ICOS-L). Deciphering these deranged immune mechanisms and how they are impacted by chemotherapy induction is essential for incorporation of novel immune-based strategies in order to restore immunity and inhibit the immunosuppressive phenotype of metastatic lung cancer.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Receptores Imunológicos/imunologia , Regulação para Cima/imunologia , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/imunologia , Antígenos Ly/imunologia , Antígeno CD11b/imunologia , Carboplatina/uso terapêutico , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Transdução de Sinais/imunologia , Ativação Transcricional/imunologia
12.
J Immunol Res ; 2019: 1278301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815149

RESUMO

Aims: To date, the ROS-generating capacities of macrophages in different activation states have not been thoroughly compared. This study is aimed at determining the nature and levels of ROS generated following stimulation with common activators of M1 and M2 macrophages and investigating the potential for this to impact fibrosis. Results: Human primary and THP-1 macrophages were treated with IFN-γ+LPS or IL-4-activating stimuli, and mRNA expression of established M1 (CXCL11, CCR7, IL-1ß) and M2 (MRC-1, CCL18, CCL22) markers was used to confirm activation. Superoxide generation was assessed by L-012-enhanced chemiluminescence and was increased in both M(IFN-γ+LPS) and M(IL-4) macrophages, as compared to unpolarised macrophages (MΦ). This signal was attenuated with NOX2 siRNA. Increased expression of the p47phox and p67phox subunits of the NOX2 oxidase complex was evident in M(IFN-γ+LPS) and M(IL-4) macrophages, respectively. Amplex Red and DCF fluorescence assays detected increased hydrogen peroxide generation following stimulation with IL-4, but not IFN-γ+LPS. Coculture with human aortic adventitial fibroblasts revealed that M(IL-4), but not M(IFN-γ+LPS), enhanced fibroblast collagen 1 protein expression. Macrophage pretreatment with the hydrogen peroxide scavenger, PEG-catalase, attenuated this effect. Conclusion: We show that superoxide generation is not only enhanced with stimuli associated with M1 macrophage activation but also with the M2 stimulus IL-4. Macrophages activated with IL-4 also exhibited enhanced hydrogen peroxide generation which in turn increased aortic fibroblast collagen production. Thus, M2 macrophage-derived ROS is identified as a potentially important contributor to aortic fibrosis.


Assuntos
Fibroblastos/efeitos dos fármacos , Interferon gama/farmacologia , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Transdução de Sinais/genética , Catalase/farmacologia , Quimiocina CCL22/genética , Quimiocina CCL22/imunologia , Quimiocina CXCL11/genética , Quimiocina CXCL11/imunologia , Quimiocinas CC/genética , Quimiocinas CC/imunologia , Técnicas de Cocultura , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-4/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Oxirredução/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Superóxidos/metabolismo , Células THP-1
13.
Anticancer Res ; 39(11): 5919-5925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704816

RESUMO

BACKGROUND/AIM: The aim of the current study was to investigate the synergistic efficacy of Robo1 bichimeric antigen receptor-natural killer cell (BiCAR-NK) immunotherapy and 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model. MATERIALS AND METHODS: The orthotopic pancreatic tumor model was established with human pancreatic cancer BxPC-3 cells expressing red fluorescent protein. The mice were treated with 125I seed implantation alone or the combination of 125I seeds with Robo1-specific CAR-NK cells. To assess tumor inhibition, in vivo fluorescence imaging was conducted. 7 Tesla magnetic resonance (7T-MR) scanning was applied to measure the changes in the metabolic profiles of tumor tissues. RESULTS: Tumor size was significantly reduced in the 125I and 125I +CAR-NK treated group compared to the untreated group (p<0.05). The 125I seed +CAR-NK treated group showed significantly higher tumor reduction than 125I seed treatment alone (p<0.05). T1 diffusion weighted imaging (T1DWI) sequence showed that the tumors of the 125I +BiCAR-NK treated group had a significantly higher grey scale value than the tumors from the untreated control and the group treated with 125I seed alone (p<0.05). CONCLUSION: Robo1 specific CAR-NK immunotherapy enhances efficacy of 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model.


Assuntos
Braquiterapia/métodos , Imunoterapia , Radioisótopos do Iodo/uso terapêutico , Células Matadoras Naturais/imunologia , Proteínas do Tecido Nervoso/imunologia , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/imunologia , Receptores Imunológicos/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Immunohorizons ; 3(11): 531-546, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732662

RESUMO

NK cell functions are tightly regulated by the balance between the inhibitory and stimulatory surface receptors. We investigated the surface expression of galectin-9 (Gal-9) and its function in NK cells from HIV-infected individuals on antiretroviral therapy, long-term nonprogressors, and progressors compared with healthy controls. We also measured the expression of TIGIT and TIM-3 on different NK cell subpopulations and compared their functionality to Gal-9 + NK cells. Our data demonstrated significant upregulation of Gal-9 on NK cells in HIV-infected groups versus healthy controls. Gal-9 expression was associated with impaired expression of cytotoxic effector molecules granzyme B, perforin, and granulysin. In contrast, Gal-9 expression significantly enhanced IFN-γ expression in NK cells of HIV-1-infected individuals. We also found an expansion of TIGIT + NK cells in HIV-infected individuals; however, dichotomous to Gal-9 + NK cells, TIGIT + NK cells expressed significantly higher amounts of cytotoxic molecules but lower IFN-γ. Moreover, lower expression of cytotoxic effector molecules in Gal-9+ NK cells was associated with higher CD107a expression, which suggests indiscriminate degranulation. Importantly, a positive correlation between the plasma viral load and Gal-9+ NK cells was observed in progressors. Finally, we found that a cytokine mixture (IL-12, IL-15, and IL-18) can improve effector functions of Gal-9+ NK cells in HIV-infected individuals, although, such an effect was observed for Gal-9- NK cells, as well. Overall, our data highlight the important role of Gal-9 in dysfunctional NK cells and, more importantly, a dichotomy for the role of Gal-9 versus TIGIT and suggest a potential new avenue for the development of therapeutic approaches.


Assuntos
Galectinas/imunologia , Infecções por HIV/imunologia , Células Matadoras Naturais/imunologia , Receptores Imunológicos/imunologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Galectinas/sangue , Granzimas/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Interferon gama/imunologia , Interleucinas/imunologia , Perforina/metabolismo , Receptores Imunológicos/sangue , Carga Viral
15.
BMC Genomics ; 20(1): 878, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747871

RESUMO

BACKGROUND: The function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for tuberculosis. We measured infection phenotypes and transcriptome responses using RNA deep sequencing in mutant and control larvae. RESULTS: tlr2 mutant embryos at 2 dpf do not show differences in numbers of macrophages and neutrophils compared to control embryos. However, we found substantial changes in gene expression in these mutants, particularly in metabolic pathways, when compared with the heterozygote tlr2+/- control. At 4 days after Mm infection, the total bacterial burden and the presence of extracellular bacteria were higher in tlr2-/- larvae than in tlr2+/-, or tlr2+/+ larvae, whereas granuloma numbers were reduced, showing a function of Tlr2 in zebrafish host defense. RNAseq analysis of infected tlr2-/- versus tlr2+/- shows that the number of up-regulated and down-regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in inflammation and immune responses, including il1b, tnfb, cxcl11aa/ac, fosl1a, and cebpb. Furthermore, RNAseq analyses revealed that the expression of genes for Maf family transcription factors, vitamin D receptors, and Dicps proteins is altered in tlr2 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling axis. CONCLUSION: The transcriptome and infection burden analyses show a function of Tlr2 as a protective factor against mycobacteria. Transcriptome analysis revealed tlr2-specific pathways involved in Mm infection, which are related to responses to Mtb infection in human macrophages. Considering its dominant function in control of transcriptional processes that govern defense responses and metabolism, the TLR2 protein can be expected to be also of importance for other infectious diseases and interactions with the microbiome.


Assuntos
Doenças dos Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/veterinária , Receptor 2 Toll-Like/genética , Peixe-Zebra/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Quimiocina CXCL11/genética , Quimiocina CXCL11/imunologia , Resistência à Doença/genética , Embrião não Mamífero , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Larva/genética , Larva/crescimento & desenvolvimento , Larva/imunologia , Larva/microbiologia , Linfotoxina-alfa/genética , Linfotoxina-alfa/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Fatores de Transcrição Maf/genética , Fatores de Transcrição Maf/imunologia , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/imunologia , Mycobacterium marinum/patogenicidade , Neutrófilos/imunologia , Neutrófilos/microbiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/imunologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/imunologia , Transcriptoma/imunologia , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/imunologia , Peixe-Zebra/microbiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia
16.
Semin Immunol ; 42: 101305, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604537

RESUMO

Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4+ and CD8+ T cells, and Tregs, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.


Assuntos
Antígenos CD/imunologia , Receptores Imunológicos/imunologia , Animais , Antígenos CD/química , Humanos , Imunoterapia , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores Imunológicos/química , Microambiente Tumoral/imunologia
17.
BMC Bioinformatics ; 20(1): 490, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601176

RESUMO

BACKGROUND: The development of accurate epitope prediction tools is important in facilitating disease diagnostics, treatment and vaccine development. The advent of new approaches making use of antibody and TCR sequence information to predict receptor-specific epitopes have the potential to transform the epitope prediction field. Development and validation of these new generation of epitope prediction methods would benefit from regularly updated high-quality receptor-antigen complex datasets. RESULTS: To address the need for high-quality datasets to benchmark performance of these new generation of receptor-specific epitope prediction tools, a webserver called SCEptRe (Structural Complexes of Epitope-Receptor) was created. SCEptRe extracts weekly updated 3D complexes of antibody-antigen, TCR-pMHC and MHC-ligand from the Immune Epitope Database and clusters them based on antigen, receptor and epitope features to generate benchmark datasets. SCEptRe also provides annotated information such as CDR sequences and VDJ genes on the receptors. Users can generate custom datasets based by selecting thresholds for structural quality and clustering parameters (e.g. resolution, R-free factor, antigen or epitope sequence identity) based on their need. CONCLUSIONS: SCEptRe provides weekly updated, user-customized comprehensive benchmark datasets of immune receptor-epitope structural complexes. These datasets can be used to develop and benchmark performance of receptor-specific epitope prediction tools in the future. SCEptRe is freely accessible at http://tools.iedb.org/sceptre .


Assuntos
Complexo Antígeno-Anticorpo , Bases de Dados de Proteínas , Epitopos/metabolismo , Receptores Imunológicos/metabolismo , Epitopos/imunologia , Humanos , Receptores Imunológicos/imunologia
18.
Nat Immunol ; 20(11): 1425-1434, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611702

RESUMO

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR-ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell-expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR-ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígenos B7/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Doenças Autoimunes/imunologia , Antígenos B7/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Quimioterapia Combinada/métodos , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Ligantes , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
19.
Mol Immunol ; 114: 553-560, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31521019

RESUMO

Cell surface display is a useful platform to examine the interactions between two proteins of interest, such as immune receptors and ligands. This technique is also useful for studies on the immune receptors of lower vertebrates and invertebrates. However, in many cases, the commonly used cell culture temperature is relatively high for proteins from such organisms. Since insect cells can be cultured at lower temperatures than many other cells, and since they are equipped with "quality control" system, which is advantageous for the presentation of properly folded proteins, we anticipated that the insect cell surface display system could be more suitable for that type of research. In the present study, multiple cloning site of the commercially available expression vector pIB/V5-His was modified, and whether this vector could be useful to present fish immune-related membrane proteins was investigated. Using this plasmid, fugu's CD8α and CC chemokine receptor 7 could be presented on the cell surface. The clones of the lamprey variable lymphocyte receptors obtained previously by the yeast surface display (YSD) system as hen's egg lysozyme (HEL) binders also could be presented on the cell surface and bound to HEL. These results suggest that functional immune-related membrane proteins can be presented on the insect cell surface, indicating that this system is useful for immunological studies on exothermal animals.


Assuntos
Membrana Celular/imunologia , Proteínas de Peixes/imunologia , Peixes/imunologia , Insetos/imunologia , Proteínas de Membrana/imunologia , Animais , Células Cultivadas , Galinhas/imunologia , Citometria de Fluxo/métodos , Lampreias/imunologia , Ligantes , Muramidase/imunologia , Receptores Imunológicos/imunologia
20.
Cell Host Microbe ; 26(2): 193-201, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415752

RESUMO

Plant innate immunity is triggered via direct or indirect recognition of pathogen effectors by the NLR family immune receptors. Mechanistic understanding of plant NLR function has relied on structural information from individual NLR domains and inferences from studies on animal NLRs. Recent reports of the cryo-EM structures of the Arabidopsis plant immune receptor ZAR1 in monomeric inactive and transition states, as well as the active oligomeric state or the "resistosome," have afforded a quantum leap in our understanding of how plant NLRs function. In this Review, we outline the recent structural findings and examine their implications for the activation of plant immune receptors more broadly. We also discuss how NLR signaling in plants, as illustrated by the ZAR1 structure, is analogous to innate immune receptor signaling mechanisms across kingdoms, drawing particular attention to the concept of signaling by cooperative assembly formation.


Assuntos
Proteínas de Arabidopsis , Proteínas de Transporte , Imunidade Vegetal/imunologia , Receptores Imunológicos , Transdução de Sinais , Difosfato de Adenosina , Trifosfato de Adenosina/metabolismo , Arabidopsis/imunologia , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Imunidade Inata , Proteínas NLR/química , Proteínas NLR/metabolismo , Imunidade Vegetal/fisiologia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Domínios Proteicos , Receptores Imunológicos/química , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo
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