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1.
Ann Hematol ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39259326

RESUMO

The Wilms' tumor protein 1 (WT1) is a well-known and prioritized tumor-associated antigen expressed in numerous solid and blood tumors. Its abundance and immunogenicity have led to the development of different WT1-specific immune therapies. The driving player in these therapies, the WT1-specific T-cell receptor (TCR) repertoire, has received much less attention. Importantly, T cells with high affinity against the WT1 self-antigen are normally eliminated after negative selection in the thymus and are thus rare in peripheral blood. Here, we developed computational models for the robust and fast identification of WT1-specific TCRs from TCR repertoire data. To this end, WT137-45 (WT1-37) and WT1126-134 (WT1-126)-specific T cells were isolated from WT1 peptide-stimulated blood of healthy individuals. The TCR repertoire from these WT1-specific T cells was sequenced and used to train a pattern recognition model for the identification of WT1-specific TCR patterns for the WT1-37 or WT1-126 epitopes. The resulting computational models were applied on an independent published dataset from acute myeloid leukemia (AML) patients, treated with hematopoietic stem cell transplantation, to track WT1-specific TCRs in silico. Several WT1-specific TCRs were found in AML patients. Subsequent clustering analysis of all repertoires indicated the presence of more diverse TCR patterns within the WT1-specific TCR repertoires of AML patients in complete remission in contrast to relapsing patients. We demonstrate the possibility of tracking WT1-37 and WT1-126-specific TCRs directly from TCR repertoire data using computational methods, eliminating the need for additional blood samples and experiments for the two studied WT1 epitopes.

2.
Drug Resist Updat ; 67: 100914, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36630862

RESUMO

AIMS: To gain insights into the underlying mechanisms of NTP therapy sensitivity and resistance, using the first-ever NTP-resistant cell line derived from sensitive melanoma cells (A375). METHODS: Melanoma cells were exposed to NTP and re-cultured for 12 consecutive weeks before evaluation against the parental control cells. Whole transcriptome sequencing analysis was performed to identify differentially expressed genes and enriched molecular pathways. Glucose uptake, extracellular lactate, media acidification, and mitochondrial respiration was analyzed to determine metabolic changes. Cell death inhibitors were used to assess the NTP-induced cell death mechanisms, and apoptosis and ferroptosis was further validated via Annexin V, Caspase 3/7, and lipid peroxidation analysis. RESULTS: Cells continuously exposed to NTP became 10 times more resistant to NTP compared to the parental cell line of the same passage, based on their half-maximal inhibitory concentration (IC50). Sequencing and metabolic analysis indicated that NTP-resistant cells had a preference towards aerobic glycolysis, while cell death analysis revealed that NTP-resistant cells exhibited less apoptosis but were more vulnerable to lipid peroxidation and ferroptosis. CONCLUSIONS: A preference towards aerobic glycolysis and ferroptotic cell death are key physiological changes in NTP-resistance cells, which opens new avenues for further, in-depth research into other cancer types.


Assuntos
Ferroptose , Glicólise , Melanoma , Gases em Plasma , Humanos , Apoptose , Linhagem Celular Tumoral , Melanoma/metabolismo , Melanoma/patologia , Melanoma/terapia , Espécies Reativas de Oxigênio/metabolismo , Gases em Plasma/uso terapêutico
3.
Int J Mol Sci ; 23(4)2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35216069

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a challenging neoplastic disease, mainly due to the development of resistance to radio- and chemotherapy. Cold atmospheric plasma (CAP) is an alternative technology that can eliminate cancer cells through oxidative damage, as shown in vitro, in ovo, and in vivo. However, how CAP affects the pancreatic stellate cells (PSCs), key players in the invasion and metastasis of PDAC, is poorly understood. This study aims to determine the effect of an anti-PDAC CAP treatment on PSCs tissue developed in ovo using mono- and co-cultures of RLT-PSC (PSCs) and Mia PaCa-2 cells (PDAC). We measured tissue reduction upon CAP treatment and mRNA expression of PSC activation markers and extracellular matrix (ECM) remodelling factors via qRT-PCR. Protein expression of selected markers was confirmed via immunohistochemistry. CAP inhibited growth in Mia PaCa-2 and co-cultured tissue, but its effectiveness was reduced in the latter, which correlates with reduced ki67 levels. CAP did not alter the mRNA expression of PSC activation and ECM remodelling markers. No changes in MMP2 and MMP9 expression were observed in RLT-PSCs, but small changes were observed in Mia PaCa-2 cells. Our findings support the ability of CAP to eliminate PDAC cells, without altering the PSCs.


Assuntos
Neoplasias Pancreáticas/terapia , Células Estreladas do Pâncreas/efeitos dos fármacos , Gases em Plasma/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Fenótipo , Microambiente Tumoral/efeitos dos fármacos
4.
Semin Cancer Biol ; 60: 41-56, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31605750

RESUMO

The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play a complex and essential role in the regulation of physiologic cell processes, such as proliferation, differentiation, apoptosis and angiogenesis, and serves to organize the epigenetic landscape of immune cells. To date, seven STAT genes have been identified in the human genome; STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. They all account for diverse effects in response to extracellular signaling proteins, mainly by altering gene transcription in the effector cells. Members of the STAT family have been implicated in human cancer development, progression, metastasis, survival and resistance to treatment. Particularly STAT3 and STAT5 are of interest in cancer biology. They are currently considered as oncogenes, but their signaling is embedded into a complex and delicate balance between different (counteracting) transcription factors, and thus, in some contexts they can have a tumor suppressive role. Assessing STAT signaling mutations as well as screening for aberrant STAT pathway activation may have a role to predict sensitivity to immunotherapy and targeted STAT inhibition. In the present comprehensive review of the literature, we discuss in-depth the role of each STAT family member in cancer, assemble cutting-edge information on the use of these molecules as potential biomarkers and targets for treatment, and address why their clinical implementation is controversy.


Assuntos
Neoplasias/metabolismo , Fatores de Transcrição STAT/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Suscetibilidade a Doenças , Humanos , Janus Quinases/metabolismo , Terapia de Alvo Molecular , Família Multigênica , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Fatores de Transcrição STAT/genética , Transdução de Sinais/efeitos dos fármacos
5.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670397

RESUMO

Even though cervical cancer is partly preventable, it still poses a great public health problem throughout the world. Current therapies have vastly improved the clinical outcomes of cervical cancer patients, but progress in new systemic treatment modalities has been slow in the last years. Especially for patients with advanced disease this is discouraging, as their prognosis remains very poor. The pathogen-induced nature, the considerable mutational load, the involvement of genes regulating the immune response, and the high grade of immune infiltration, suggest that immunotherapy might be a promising strategy to treat cervical cancer. In this literature review, we focus on the use of PD-1 blocking therapy in cervical cancer, pembrolizumab in particular, as it is the only approved immunotherapy for this disease. We discuss why it has great clinical potential, how it opens doors for personalized treatment in cervical cancer, and which trials are aiming to expand its clinical use.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Proteínas de Neoplasias/antagonistas & inibidores , Recidiva Local de Neoplasia/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias do Colo do Útero/terapia , Feminino , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia
6.
Br J Cancer ; 123(5): 752-761, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32541873

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed by 80-90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC. METHODS: In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA. RESULTS: While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC. CONCLUSION: These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.


Assuntos
Cetuximab/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Infecções por Papillomavirus/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
7.
Cancer Immunol Immunother ; 69(5): 867-877, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31970440

RESUMO

Acute lymphoblastic leukaemia (ALL) in adults is a rare and difficult-to-treat cancer that is characterised by excess lymphoblasts in the bone marrow. Although many patients achieve remission with chemotherapy, relapse rates are high and the associated impact on survival devastating. Most patients receive chemotherapy and for those whose overall fitness supports it, the most effective treatment to date is allogeneic stem cell transplant that can improve overall survival rates in part due to a 'graft-versus-leukaemia' effect. However, due to the rarity of this disease, and the availability of mature B-cell antigens on the cell surface, few new cancer antigens have been identified in adult B-ALL that could act as targets to remove residual disease in first remission or provide alternative targets for escape variants if and when current immunotherapy strategies fail. We have used RT-PCR analysis, literature searches, antibody-specific profiling and gene expression microarray analysis to identify and prioritise antigens as novel targets for the treatment of adult B-ALL.


Assuntos
Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Imunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Evasão Tumoral/efeitos dos fármacos , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/isolamento & purificação , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Indução de Remissão/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Evasão Tumoral/imunologia
8.
Genes Immun ; 20(3): 255-260, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29904098

RESUMO

Pathogens of past and current infections have been identified directly by means of PCR or indirectly by measuring a specific immune response (e.g., antibody titration). Using a novel approach, Emerson and colleagues showed that the cytomegalovirus serostatus can also be accurately determined by using a T cell receptor repertoire data mining approach. In this study, we have sequenced the CD4+ memory T cell receptor repertoire of a Belgian cohort with known cytomegalovirus serostatus. A random forest classifier was trained on the CMV specific T cell receptor repertoire signature and used to classify individuals in the Belgian cohort. This study shows that the novel approach can be reliably replicated with an equivalent performance as that reported by Emerson and colleagues. Additionally, it provides evidence that the T cell receptor repertoire signature is to a large extent present in the CD4+ memory repertoire.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Mineração de Dados/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Testes Sorológicos/métodos , Adulto , Infecções por Citomegalovirus/sangue , Humanos , Memória Imunológica , Receptores de Antígenos de Linfócitos T/genética , Testes Sorológicos/normas
9.
Cancer Immunol Immunother ; 68(10): 1573-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31511925

RESUMO

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.


Assuntos
Antígeno B7-H1/fisiologia , Fibromatose Agressiva/imunologia , Tolerância Imunológica , Adolescente , Adulto , Idoso , Antígenos CD20/análise , Ligante CD27/análise , Feminino , Fibromatose Agressiva/patologia , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral , Adulto Jovem
10.
Blood ; 130(15): 1713-1721, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28830889

RESUMO

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Leucemia Mieloide Aguda/prevenção & controle , Leucemia Mieloide Aguda/terapia , Vacinação , Idoso , Biomarcadores Tumorais/metabolismo , Citocinas/metabolismo , Intervalo Livre de Doença , Eletroporação , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/imunologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Recidiva , Indução de Remissão , Resultado do Tratamento , Proteínas WT1/genética , Proteínas WT1/metabolismo
11.
Invest New Drugs ; 37(5): 890-901, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30547315

RESUMO

Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.


Assuntos
Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glucocorticoides/farmacocinética , Lipossomos/química , Melanoma Experimental/tratamento farmacológico , Polietilenoglicóis/química , Prednisolona/análogos & derivados , Animais , Apoptose , Proliferação de Células , Modelos Animais de Doenças , Glucocorticoides/administração & dosagem , Humanos , Cinética , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Prednisolona/administração & dosagem , Prednisolona/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas
12.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455014

RESUMO

In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination with ICP blocking antibodies. Cisplatin, oxaliplatin and pemetrexed are interesting chemotherapeutic agents to combine with immunotherapy given their immunomodulatory capacities. We looked into cisplatin and pemetrexed because their combination is used as first-line treatment of MPM. Additionally, the effect of the immunogenic chemotherapeutic agent, oxaliplatin, was also studied. Three different MPM cell lines were used for representation of both epithelioid and sarcomatoid subtypes. The desired inhibitory concentrations of the chemotherapeutic agents were determined with the SRB-assay. Allogeneic co-cultures of MPM cells with healthy donor peripheral blood mononuclear cells (PBMC) were set up to assess the effect of these chemotherapeutic agents on the expression of ICPs (PD-1, LAG-3, TIM-3) and their ligands (PD-L1, PD-L2, galectin-9). Cisplatin might be a promising treatment to combine with ICP blocking antibodies since our MPM cell lines were most susceptible to this stand-alone treatment. We found that the expression of ICPs and their ligands on both MPM cells and PBMC was mostly downregulated or unaltered when treated with chemotherapeutic agents, though no clear trend could be determined.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Mesotelioma/etiologia , Mesotelioma/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/antagonistas & inibidores , Linhagem Celular Tumoral , Terapia Combinada , Expressão Gênica , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mesotelioma/patologia , Mesotelioma/terapia , Mesotelioma Maligno , Terapia de Alvo Molecular , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052546

RESUMO

RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.


Assuntos
Ligante RANK/imunologia , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Neoplasias do Colo do Útero/imunologia , Animais , Colo do Útero/imunologia , Colo do Útero/patologia , Feminino , Humanos , Imunoterapia/métodos , Ligante RANK/análise , Receptor Ativador de Fator Nuclear kappa-B/análise , Transdução de Sinais , Microambiente Tumoral , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia
14.
Immunogenetics ; 70(6): 363-372, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29196796

RESUMO

Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We created a computational model for the Human Leukocyte Antigen (HLA-A, -B, and -C) presentation capacity of peptides derived from the VZV Immediate Early 62 (IE62) protein. This model could then be applied to a HZ cohort with known HLA molecules. We found that HLA-A molecules with poor VZV IE62 presentation capabilities were more common in a cohort of 50 individuals with a history of HZ compared to a nationwide control group, which equated to a HZ risk increase of 60%. This tendency was most pronounced for cases of HZ at a young age, where other risk factors are less prevalent. These findings provide new molecular insights into the development of HZ and reveal a genetic predisposition in those individuals most at risk to develop HZ.


Assuntos
Antígenos HLA-A/imunologia , Herpes Zoster/imunologia , Herpesvirus Humano 3/imunologia , Proteínas Imediatamente Precoces/imunologia , Transativadores/imunologia , Proteínas do Envelope Viral/imunologia , Adulto , Idoso , Bélgica/epidemiologia , Varicela/imunologia , Varicela/virologia , Feminino , Predisposição Genética para Doença , Herpes Zoster/epidemiologia , Herpes Zoster/genética , Humanos , Proteínas Imediatamente Precoces/genética , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Fatores de Risco , Transativadores/genética , Proteínas do Envelope Viral/genética
15.
Pharmacol Rev ; 67(4): 731-53, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26240218

RESUMO

Although the earliest­rudimentary­attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy.


Assuntos
Células Dendríticas/metabolismo , Imunoterapia Ativa/métodos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva/métodos , Anticorpos Monoclonais , Antígenos de Neoplasias/imunologia , Apoptose , Vacinas Anticâncer/imunologia , Técnicas de Cultura de Células , Citocinas/biossíntese , Células Dendríticas/imunologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Humanos , Células Matadoras Naturais/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Transdução de Sinais
16.
Histopathology ; 71(3): 357-365, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28383817

RESUMO

AIMS: During recent years, immune checkpoint inhibition has proved to be effective in several solid malignancies. The aim of this study was to identify novel targets for immunotherapy in anaplastic thyroid cancer by analysis of the expression of tumour antigens for which therapeutic agents are available. METHOD AND RESULTS: By immunohistochemistry we observed tumoral expression of CD70 in 49% of cases. Expression of its receptor, CD27, was present mainly in lymphocytes surrounding and infiltrating the tumour and observed only rarely in tumour cells. CD70 expression was associated with the presence of a precursor papillary thyroid carcinoma and the presence of BRAF V600E mutations in the anaplastic thyroid cancer lesion. Furthermore, the expression of CD70 seems stable during progression of the disease. Tumoral expression of programmed cell death ligand 1 (PD-L1) was found in 28.6% of the anaplastic thyroid cancer cases. Programmed cell death 1 (PD-1), the receptor of PD-L1, was not expressed on the tumour cells. No association between CD70 expression and PD-L1 expression could be demonstrated. CONCLUSION: These data suggest that targeted immunotherapy for CD70/CD27 and PD-L1/PD-1 might be promising in anaplastic thyroid cancer. However, as a low amount of tumour-infiltrating lymphocytes was observed in most lesions, combined therapy with agents enhancing the invasion of lymphocytes in the tumour region needs to be considered.


Assuntos
Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/análise , Ligante CD27/biossíntese , Imunoterapia/métodos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Adulto , Idoso , Antígenos de Neoplasias/análise , Antígeno B7-H1/análise , Ligante CD27/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Trends Immunol ; 35(1): 38-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24262387

RESUMO

Dendritic cells (DCs) are a family of professional antigen-presenting cells (APCs) that are able to initiate innate and adaptive immune responses against pathogens and tumor cells. The DC family is heterogeneous and is classically divided into two main subsets, each with its unique phenotypic and functional characteristics: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). Recent results have provided intriguing evidence that both DC subsets can also function as direct cytotoxic effector cells; in particular, against cancer cells. In this review, we delve into this understudied function of human DCs and discuss why these so-called killer DCs might become important tools in future cancer immunotherapies.


Assuntos
Citotoxicidade Imunológica , Células Dendríticas/imunologia , Neoplasias/imunologia , Imunidade Adaptativa , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Humanos , Imunoterapia , Neoplasias/metabolismo , Neoplasias/terapia , Fenótipo
18.
Cancer Immunol Immunother ; 64(7): 831-42, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25863943

RESUMO

Dendritic cell (DC) vaccination has demonstrated potential in clinical trials as a new effective cancer treatment, but objective and durable clinical responses are confined to a minority of patients. Interferon (IFN)-α, a type-I IFN, can bolster anti-tumor immunity by restoring or increasing the function of DCs, T cells and natural killer (NK) cells. Moreover, type-I IFN signaling on DCs was found to be essential in mice for tumor rejection by the innate and adaptive immune system. Targeted delivery of IFN-α by DCs to immune cells could boost the generation of anti-tumor immunity, while avoiding the side effects frequently associated with systemic administration. Naturally circulating plasmacytoid DCs, major producers of type-I IFN, were already shown capable of inducing tumor antigen-specific T cell responses in cancer patients without severe toxicity, but their limited number complicates their use in cancer vaccination. In the present work, we hypothesized that engineering easily generated human monocyte-derived mature DCs to secrete IFN-α using mRNA electroporation enhances their ability to promote adaptive and innate anti-tumor immunity. Our results show that IFN-α mRNA electroporation of DCs significantly increases the stimulation of tumor antigen-specific cytotoxic T cell as well as anti-tumor NK cell effector functions in vitro through high levels of IFN-α secretion. Altogether, our findings mark IFN-α mRNA-electroporated DCs as potent inducers of both adaptive and innate anti-tumor immunity and pave the way for clinical trial evaluation in cancer patients.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Interferon-alfa/metabolismo , Proteínas WT1/imunologia , Antígenos de Neoplasias/genética , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/genética , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/transplante , Eletroporação , Humanos , Imunoterapia Adotiva , Interferon-alfa/genética , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Neoplasias/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Proteínas WT1/genética
19.
J Liposome Res ; 25(1): 46-57, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24984229

RESUMO

Besides the development of sample preparation methods for the determination of separate liposomal-encapsulated prednisolone phosphate and non-encapsulated prednisolone concentrations in murine plasma and blood, this article also presents the first description of an accurate sample preparation method for the determination of such separate concentrations in the murine liver. The quantitative differentiation is based on the immediate hydrolysis of prednisolone phosphate (PP) into prednisolone (P) after its release from the liposomes in vivo: PP represents the encapsulated drug, while P represents the non-encapsulated drug. The use of 10 ml methanol/g tissue during homogenization of liver tissue ensures complete liposome rupture, prevention of the dephosphorylation of PP released during homogenization, sufficient clean supernatants, excellent extraction of P and sufficient extraction of PP and excellent accuracies and precision complying with the internal guidelines for pre-clinical studies (80-120% and maximal 20%, respectively). Similarly, the matching sample preparation methods for plasma and blood involve protein precipitation with four equivalents of methanol also ensuring accuracies and precision complying with the internal guidelines for pre-clinical studies. Application of these sample preparation methods is going to generate the first pharmacokinetic (PK) profile of a liposomal preparation, in which the encapsulated and non-encapsulated drug concentrations in a tissue are measured separately. Such separated concentration profiles can gain important insights into the PKs of liposomal PP and probably also with regard to liposomal formulations in general, like the quantification of the in vivo drug release from the liposomes.


Assuntos
Glucocorticoides/química , Fígado , Prednisolona/análogos & derivados , Animais , Análise Química do Sangue , Coleta de Amostras Sanguíneas , Criopreservação , Lipossomos , Masculino , Camundongos Endogâmicos C57BL , Prednisolona/química , Solventes
20.
Lancet Oncol ; 15(7): e257-67, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24872109

RESUMO

Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. Dendritic cell-based immunotherapy is safe and can induce antitumour immunity, even in patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour response rates rarely exceeding 15%. Paradoxically, findings from emerging research indicate that dendritic cell-based vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical potency of dendritic cell-based vaccination. We review the clinical effectiveness of dendritic cell-based vaccine therapy in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated into clinical trials to leverage the clinical effectiveness of dendritic cell-based cancer immunotherapy. Specifically, we discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies.


Assuntos
Células Dendríticas/imunologia , Imunoterapia , Neoplasias/terapia , Humanos , Imunoterapia/efeitos adversos , Neoplasias/imunologia , Neoplasias/mortalidade , Carga Tumoral , Vacinação
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