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1.
Anticancer Res ; 39(10): 5369-5374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570431

RESUMO

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are ex vivo expanded major histocompatibility complex (MHC)-unrestricted cytotoxic cells with promising effects against a variety of cancer types. Regulatory T-cells (T-reg) have been shown to reduce the effectiveness of CIK cells against tumor cells. Peptide P60 has been shown to inhibit the immunosuppressive functions of T-regs. This study aimed at examining the effect of p60 on CIK cells efficacy against renal and pancreatic cancer cells. MATERIALS AND METHODS: The effect of P60 on CIK cytotoxicity was examined using flow cytometry, WST-8-based cell viability assay and interferon γ (IFNγ) ELISA. RESULTS: P60 treatment resulted in a significant decrease in the viability of renal and pancreatic cancer cell lines co-cultured with CIK cells. No increase in IFNγ secretion from CIK cells was detected following treatment with P60. P60 caused no changes in the distribution of major effector cell populations in CIK cell cultures. CONCLUSION: P60 may potentiate CIK cell cytotoxicity against tumor cells.


Assuntos
Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Fatores de Transcrição Forkhead/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura/métodos , Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
2.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484350

RESUMO

Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor activity and are capable of eradicating tumors with few side effects. They are a very encouraging cell population used against hematological and solid tumors, with an inexpensive expansion protocol which could yield to superior clinical outcome in clinical trials employing adoptive cellular therapy combination. In the last decade, clinical protocols have been modified by enriching lymphocytes with CIK cells. They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells. CIK cells are mainly used in two diseases: in hematological patients who suffer relapse after allogeneic transplantation and in patients with hepatic carcinoma after surgical ablation to eliminate residual tumor cells. Dendritic cells DCs could play a pivotal role in enhancing the antitumor efficacy of CIKs.


Assuntos
Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica , Células Dendríticas/metabolismo , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais/metabolismo
3.
Front Biosci (Landmark Ed) ; 24: 1259-1270, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136978

RESUMO

Studies have shown that CD4+ CD25+ regulatory T cells (Tregs) could inhibit cytokine-induced killer (CIK) cells against tumor cells, but minimal data have been reported on the underlying mechanisms. The purpose of this study was to investigate the potential suppressive mechanisms of cord blood Tregs on CIK cells in vivo and in vitro. The in vitro study demonstrated that Tregs were normally proliferated and had potent suppressive characteristics. CD4+ CD25+ LAP+ cells were highly expressed as part of activated Tregs, which limited CIK cell-mediated cytotoxicity and reduced the expression of the NKG2D receptor. Interestingly, the inhibitory ability of Tregs could be mimicked by soluble TGF-ß1 and neutralizing TGF-ß1 antibody could abrogate the inhibitory function of Tregs on CIK cells. In vivo results showed that adoptively transferred CIK cells could delay the tumor growth in nude mice. Moreover, depletion of CD4+ CD25+ Tregs in preculture or blockade of TGF-beta 1 strikingly enhanced CIK cells cytotoxicity. These data indicate that Tregs inhibit CIK cells cytotoxicity mainly by down regulating the expression of NKG2D receptor in a TGF-ß dependent manner.


Assuntos
Anticorpos Neutralizantes/farmacologia , Células Matadoras Induzidas por Citocinas/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Neoplasias/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica/imunologia , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células K562 , Camundongos Endogâmicos BALB C , Camundongos Nus , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Blood Rev ; 35: 18-31, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30826141

RESUMO

Significant improvements in the survival of patients with hematological cancers following hematopoietic stem cell transplantation provide evidence supporting the potency of immune cell-mediated anti-leukemic effects. Studies focusing on immune cell-based cancer therapies have made significant breakthroughs in the last few years. Adoptive cellular therapy (ACT), and chimeric antigen receptor (CAR) T cell therapy, in particular, has significantly increased the survival of patients with B cell acute lymphoblastic leukemia and aggressive B cell lymphoma. Despite antigen-negative relapses and severe toxicities such as cytokine release syndrome after treatment, CAR-T cell therapies have been approved by the FDA in some conditions. Although a number of studies have tried to achieve similar results for acute myeloid leukemia (AML), clinical outcomes have not been as promising. In this review, we summarize recent and ongoing studies on cellular therapies for AML patients, with a focus on antigen-specific versus -nonspecific approaches.


Assuntos
Imunoterapia Adotiva , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Animais , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Epitopos de Linfócito T/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
5.
Cell Prolif ; 52(3): e12594, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30847992

RESUMO

OBJECTIVE: Ex vivo expansion is an effective way to produce cytokine-induced killer (CIK) cells needed for clinical trials. Here, ex vivo expansion and metabolism characters of CIK cells in static and dynamic cultures and the relationship between cell expansion and metabolism were investigated. MATERIALS AND METHODS: Oxygen transfer efficiency was assessed by computational fluid dynamics technique. Cell phenotype, apoptosis and of transporter expression were determined by flow cytometry and Western blotting. Metabolites and enzyme activities were assessed by biochemical methods. RESULTS: Dynamic cultures favoured better CIK cell expansion without impairing their phenotype and cytotoxicity, enhanced oxygen transfer efficiency. The glucose metabolism flux of cells in dynamic cultures was enhanced by upregulating surface glucose transporter 1 expression and phosphofructokinase activity. Moreover, pentose phosphate pathway (PPP) metabolic flux was enhanced through upregulating glucose-6-phosphate dehydrogenase activity. Glutaminolysis was also accelerated via boosting glutamine transporters expression, glutaminase (GLS) and glutamate dehydrogenase activities. Together with higher oxygen consumption rate and extracellular acidification rate, it was suggested that cells in dynamic cultures were in a more vigorous metabolic state for ATP production. CONCLUSION: Dynamic cultures accelerated glucose and glutamine metabolic flux to promote ATP production, elevated glucose metabolic flux through PPP to promote biosynthesis for better cell expansion. These findings may provide the basis for ex vivo CIK cell expansion process optimization.


Assuntos
Trifosfato de Adenosina/biossíntese , Células Matadoras Induzidas por Citocinas/metabolismo , Via de Pentose Fosfato , Técnicas de Cultura de Células , Proliferação de Células , Células Matadoras Induzidas por Citocinas/citologia , Células Matadoras Induzidas por Citocinas/imunologia , Sangue Fetal/citologia , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glutamina/metabolismo , Glicólise , Humanos , Imunoterapia Adotiva , Modelos Biológicos , Neoplasias/imunologia , Neoplasias/terapia , Consumo de Oxigênio
6.
J Cancer Res Clin Oncol ; 145(5): 1123-1132, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796510

RESUMO

PURPOSE: Adenovirus (Ads) is one of the most popular vectors used in gene therapy for the treatment of cancer. However, systemic therapy is limited by circulating antiviral antibodies and poor viral delivery in vivo. In this study, we used cytokine-induced killer (CIK) cells as delivery vehicles of Ads KGHV500 carrying the anti-p21Ras scFv gene to treat Ras gene-related lung cancer and investigate the anti-tumor effect in vitro and in vivo. METHODS: The human lung cancer cell line A549 was employed to investigate the anti-tumor activity of recombinant Ads KGHV500 harboring the anti-p21Ras scFv gene using MTT, wound healing, transwell invasion, and apoptosis assays in vitro. Next, CIK cells were used as delivery vehicles to deliver KGHV500 carrying the anti-p21Ras scFv gene to treat A549-transplanted tumors in nude mice, and viral replication, p21Ras scFv expression, and the therapeutic efficacy were assessed. RESULTS: In vitro studies showed that KGHV500 had potent anti-tumor activity. In addition, in vivo, this combination therapy significantly inhibited the growth of lung cancer xenografts compared with mice treated with KGHV500 alone. KGHV500 and anti-p21Ras scFv were observed in tumor tissue, but were nearly undetectable in normal tissues. CONCLUSIONS: The co-delivery of anti-p21Ras scFv by CIK cells and KGHV500 could increase the anti-tumor effect and safety, and possess considerable advantages for the treatment of Ras-related cancer.


Assuntos
Adenoviridae/genética , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Testes Imunológicos de Citotoxicidade , Modelos Animais de Doenças , Feminino , Expressão Gênica , Terapia Genética , Vetores Genéticos/genética , Humanos , Imuno-Histoquímica , Imunoterapia Adotiva , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Camundongos , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 18(1): 1087, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419845

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal cancer. CRC gene therapy mediated by adenovirus holds great promise for the treatment of malignancies. However, intravenous delivery of adenovirus exhibits limited anti-tumor activity in vivo when used alone. METHODS: In this study, the antitumor activity of the recombinant adenovirus KGHV500 was assessed with the MTT, TUNEL, Matrigel invasion and cell migration assays. To enhance the intravenous delivery of KGHV500 in vivo, cytokine-induced killer (CIK) cells were used as a second vector to carry KGHV500. We explored whether CIK cells could carry the recombinant adenovirus KGHV500 containing the anti-p21Ras single chain fragment variable antibody (scFv) gene into tumors and enhance antitumor potency. RESULTS: Our results showed that KGHV500 exhibited significant antitumor activity in vitro. In the nude mouse SW480 tumor xenograft model, the combination of CIK cells with KGHV500 could induce higher antitumor activity against colorectal cancer in vivo than that induced by either CIK or KGHV500 alone. After seven days of treatment, adenovirus and scFv were detected in tumor tissue but were not detected in normal tissues by immunohistochemistry. Therefore, KGHV500 replicates in tumors and successfully expresses anti-p21Ras scFv in a colorectal cancer xenograft model. CONCLUSIONS: Our study provides a novel strategy for the treatment of colorectal cancer by combining CIK cells with the recombinant adenovirus KGHV500 which carried anti-p21 Ras scFv.


Assuntos
Adenoviridae , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Vetores Genéticos , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Anticorpos de Cadeia Única/farmacologia , Adenoviridae/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Efeito Citopatogênico Viral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Imunoterapia Adotiva , Camundongos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Anticorpos de Cadeia Única/genética , Resultado do Tratamento , Ligação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Biotechnol ; 287: 8-17, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30273619

RESUMO

Ex vivo expansion is an effective strategy to acquire cytokine-induced killer (CIK) cells needed for clinical trials. In this work, the effects of dynamic suspension culture, which was carried out by shake flasks on a shaker, on CIK cells were investigated by the analysis of expansion characteristics and physiological functions, with the objective to optimize the culture conditions for ex vivo expansion of CIK cells. The results showed that the expansion folds of total cells in dynamic cultures reached 69.36 ± 30.36 folds on day 14, which were significantly higher than those in static cultures (9.24 ± 1.12 folds, P < 0.05), however, the proportions of CD3+ cells and CD3+CD56+ cells in both cultures were similar, leading to much higher expansion of CD3+ cells and CD3+CD56+ cells in dynamic cultures. Additionally, expanded CIK cells in two cultures possessed comparable physiological functions. Notably, significantly higher percentages of CD25+ cells and CD69+ cells were found in dynamic cultures (P < 0.05). Besides, much higher glucose consumption rate of cells (P < 0.05) but similar YLac/gluc were observed in dynamic cultures. Further, cells in dynamic cultures had better glucose utilization efficiency. Together, these results suggested that dynamic cultures improved cell activation, then accelerated glucose consumption rate, which enhanced cell expansion and promoted glucose utilization efficiency of cells.


Assuntos
Técnicas de Cultura de Células/métodos , Células Matadoras Induzidas por Citocinas/citologia , Células Matadoras Induzidas por Citocinas/metabolismo , Glucose/metabolismo , Antígenos CD/metabolismo , Terapia Baseada em Transplante de Células e Tecidos , Células Matadoras Induzidas por Citocinas/fisiologia , Citometria de Fluxo , Humanos , Fatores de Tempo
9.
Crit Rev Oncog ; 23(3-4): 219-234, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30311576

RESUMO

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies in southern China and Southeast Asia. Unfortunately, 70% of NPC patients have locally advanced disease at the first diagnosis. Radiotherapy alone and concurrent chemoradiotherapy are important treatment approaches for NPC, but they have a limited effect on patients with locally advanced or distantly metastatic disease. 1-5 Nevertheless, the unique immune environment of the EBV-associated NPC provides rational targets for immunotherapy. Diverse types of immunotherapies are actively being studied, including adoptive immunotherapy, therapeutic vaccines, immune checkpoint inhibitors, lytic-induction therapy, and viral immunotherapy. Specifically, adoptive immunotherapy with lymphocyte infusion was well tolerated and effective in 71.4% of patients combined with first-line chemotherapy. Several therapeutic vaccines and PD-1/PD-L1 pathway checkpoint inhibitors have shown promising clinic outcomes at phase I/II clinical trials. Moreover, EBV-lytic inducing therapy and viral immunotherapy for NPC are also being investigated. In this review, we summarized the current status, advantages, and disadvantages of each immunotherapy for EBV-associated NPC, which may shed light on developing safer and more effective treatment modalities in the future.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Imunoterapia , Carcinoma Nasofaríngeo/etiologia , Carcinoma Nasofaríngeo/terapia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Transformação Celular Viral , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular/métodos , Carcinoma Nasofaríngeo/diagnóstico
10.
J Biol Chem ; 293(51): 19600-19612, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30333226

RESUMO

Several clinical immunotherapy trials with cytokine-induced killer (CIK) cells have been reported. However, molecular evidence of cell expansion, acquisition of tumor cytotoxicity, and safety of CIK cells is required before putting them to clinical use. Here, we performed dynamic transcriptomic analyses of CIKs generated from primary peripheral blood mononuclear cells exposed to interferon-γ, OKT3, and interleukin-2. CIK mRNAs were extracted and sequenced at days 0, 1, 7, and 14 and subjected to bioinformatics analyses. Using weighted correlation network analysis (WGCNA), we identified two major gene modules that mediate immune cell activation and mitosis. We found that activation and cytotoxicity of CIK cells likely rely on cluster of differentiation 8 (CD8) and its protein partner LCK proto-oncogene, Src family tyrosine kinase (LCK). A time-course series analysis revealed that CIK cells have relatively low immunogenicity because of decreased expression of some self-antigens. Importantly, we identified several crucial activating receptors and auxiliary adhesion receptors expressed on CIK cells that may function as tumor sensors. Interestingly, cytotoxicity-associated genes, including those encoding PRF1, GZMB, FASL, and several cytokines, were up-regulated in mature CIK cells. Most immune-checkpoint molecules and inflammatory tumor-promoting factors were down-regulated in the CIK cells, suggesting efficacy and safety in future clinical trials. Notably, insulin-like growth factor 1 (IGF-1) was highly expressed in CIK cells and may promote cytotoxicity, although it also could facilitate tumorigenesis. The transcriptomic atlas of CIK cells presented here may inform efforts to improve CIK-associated tumor cytotoxicity and safety in clinical trials.


Assuntos
Células Matadoras Induzidas por Citocinas/metabolismo , Perfilação da Expressão Gênica , Ciclo Celular/genética , Ciclo Celular/imunologia , Linhagem Celular , Células Matadoras Induzidas por Citocinas/citologia , Células Matadoras Induzidas por Citocinas/imunologia , Humanos , Imunoterapia/efeitos adversos , Família Multigênica/genética , Família Multigênica/imunologia , Segurança , Análise de Sequência de RNA
11.
J Cancer Res Ther ; 14(Supplement): S427-S432, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29970701

RESUMO

Objective: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine-induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. Materials and Methods: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). Results: At a median follow-up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3-year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. Conclusions: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Imunoterapia Adotiva , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Terapia Combinada , Células Matadoras Induzidas por Citocinas/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia Adotiva/métodos , Indóis/administração & dosagem , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Cuidados Pós-Operatórios , Pirróis/administração & dosagem , Estudos Retrospectivos , Sorafenibe , Sunitinibe , Análise de Sobrevida , Resultado do Tratamento
12.
Biomaterials ; 170: 1-11, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29635107

RESUMO

The cytotoxicity and unique tumor-tropic properties of cytokine-induced killer (CIK) cells render them promising in the field of cancer immunotherapy and delivery systems. Here, we report a novel and facile approach to assemble gold nanoclusters (GNCs) into stable and monodispersed nanoparticles (NPs) using Chlorin e6 (Ce6) molecules. Notably, the fluorescence intensity of the GNCs-Ce6 NPs was about 4.5 folds stronger than the GNCs counterparts. The as-prepared GNCs-Ce6 NPs were conjugated with CD3 antibody (Ab) and further employed to label CIK cells to create a CIK cell-based drug delivery system (Ce6-GNCs-Ab-CIK). The Ce6-GNCs-Ab-CIK exhibited high tumor-targeting efficiency and excellent therapeutic efficacy toward MGC-803 tumor-bearing mice. Benefiting from the synergistic therapeutic effect between GNCs-Ce6-Ab NPs and CIK cells, the GNCs-Ce6-Ab-CIK strategy may present an ideal cancer theranostic platform for tumor targeted imaging and combination therapy.


Assuntos
Células Matadoras Induzidas por Citocinas/metabolismo , Ouro/química , Imunoterapia , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Fotoquimioterapia , Porfirinas/farmacologia , Animais , Anticorpos/farmacologia , Linhagem Celular Tumoral , Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias/patologia , Fenótipo
13.
Anticancer Drugs ; 29(4): 353-363, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29420334

RESUMO

Previous studies have shown that interleukin-24 (IL-24) has tumor-suppressing activity by multiple pathways. However, the immunogenicity moderation effect of IL-24 on malignant cells has not been explored extensively. In this study, we investigated the role of IL-24 in immunogenicity modulation of the myelogenous leukemia cells. Data show that myelogenous leukemia cells express low levels of immunogenicity molecules. Treatment with IL-24 could enhance leukemia cell immunogenicity, predominantly regulate leukemia cells to produce immune-associated cytokines, and improve the cytotoxic sensitivity of these cells to immune effector cells. IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. Moreover, IL-24 had marked effects on downregulating the expression of angiogenesis-related proteins vascular endothelial growth factor, cluster of differentiation (CD) 31, CD34, collagen IV and metastasis-related factors CD147, membrane type-1 matrix metalloproteinase (MMP), and MMP-2 and MMP-9 in transplanted tumors. These findings indicated novel functions of this antitumor gene and characterized IL-24 as a promising agent for further clinical trial for hematologic malignancy immunotherapy.


Assuntos
Adjuvantes Imunológicos/farmacologia , Imunomodulação , Interleucinas/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Inibidores da Angiogênese/imunologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Humanos , Interleucinas/imunologia , Interleucinas/farmacologia , Leucemia Mieloide/imunologia , Camundongos , Camundongos Nus , Células Mieloides/imunologia , Invasividade Neoplásica/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 18(11)2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29135940

RESUMO

Grass carp (Ctenopharyngodon idellus) is an important worldwide commercial freshwater culture species. However, grass carp reovirus (GCRV) causes serious hemorrhagic disease in fingerlings and yearlings of fishes. To understand the molecular pathogenesis of host cells during GCRV infection, intensive proteomic quantification analysis of lysine acetylation in Ctenopharyngodon idella kidney (CIK) cells was performed. Using dimethylation labeling-based quantitative proteomics, 832 acetylated proteins with 1391 lysine acetylation sites were identified in response to GCRV infection, among which 792 proteins with 1323 sites were quantifiable. Bioinformatics analysis showed that differentially expressed lysine acetylated proteins are involved in diverse cellular processes and associated with multifarious functions, suggesting that extensive intracellular activities were changed upon viral infection. In addition, extensive alterations on host-protein interactions at the lysine acetylation level were also detected. Further biological experiments showed that the histone deacetylases (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) could significantly suppress the GCRV replication. To our knowledge, this is the first to reveal the proteome-wide changes in host cell acetylome with aquatic virus infection. The results provided in this study laid a basis for further understanding the host response to aquareovirus infection in the post-translational modification aspect by regulating cell lysine acetylation conducive to viral replication.


Assuntos
Carpas/fisiologia , Células Matadoras Induzidas por Citocinas/metabolismo , Células Matadoras Induzidas por Citocinas/virologia , Doenças dos Peixes/virologia , Lisina/metabolismo , Proteômica , Reoviridae/fisiologia , Acetilação , Motivos de Aminoácidos , Animais , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Linhagem Celular , Análise por Conglomerados , Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Doenças dos Peixes/metabolismo , Proteínas de Peixes/química , Proteínas de Peixes/metabolismo , Ontologia Genética , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Domínios Proteicos , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteoma/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Frações Subcelulares/metabolismo , Replicação Viral/efeitos dos fármacos , Vorinostat
15.
Cancer Biomark ; 20(4): 609-615, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-28869441

RESUMO

OBJECTIVE: To investigate the improvement of cytotoxicity of autologous CIKs from patients with breast cancer to MCF-7 cells by suppressed PD-1 expression. METHODS: The Lentiviral Vector/PD-1 carrying the gene that can suppressed PD-1 was transferred to CIK cells from patients with breast cancer to inhibit PD-1 expression. The PD-1 protein were detected by RT-PCR and Western blot. The positive PD-1 of CIKs and PD-L1 of MCF-7 cells were detected by FCM, and cytotoxicity of CIKs to MCF-7 was assayed by CCK-8. RESULTS: The PD-1 positive CIKs with Lentiviral Vector/PD-1 transferred from patients with breast cancer were 16.02%, 14.36% and 14.64% at 14th, 21st and 28th day, obviously inhibited as compared to 50.54%, 74.50% and 73.36% in CIKs without transinfection (P< 0.05); the Lentiviral Vector/PD-1 decreased the PD-1 mRNA levels in CIK cells, and Lentiviral Vector/PD-1-transferred CIKs had lower PD-1 expression; CCK-8 detection showed that at 14th day, the cytotoxicity rates of CIKs with blank plasmids and those with PD-1 transfection to MCF-7 cells were 58.78% and 68.14%, respectively. CONCLUSION: MCF-7 cells have a strong PD-L1 expression at its surface, and inhibition of PD-1 expression can improve the cytotoxicity of CIK cells.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica/genética , Regulação da Expressão Gênica , Receptor de Morte Celular Programada 1/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Células MCF-7 , Receptor de Morte Celular Programada 1/metabolismo , Transfecção
16.
Cancer Biother Radiopharm ; 32(6): 221-226, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28820635

RESUMO

AIM: To evaluate the efficacy and safety of postoperative adjuvant immunotherapy with cytokine-induced killer (CIK) cells in combination with chemotherapy (CT) in colorectal cancer (CRC) patients. MATERIALS AND METHODS: A total of 46 patients were randomly assigned to either group 1 (control group) or group 2 (CIK group) using blocked randomization. Both groups received the FOLFOX4 (5-fluorouridine, leucovorin, and oxaliplatin) CT. In the CIK group, patients were given CIK cell infusion after FOLFOX4 CT. Treatment efficacy, adverse effects, and quality of life (QOL) were assessed. RESULTS: During the first 2 years of follow-up, the recurrence rate in the CIK group (26.1%, 6 in 23 cases) was significantly lower than the control group (43.5%, 10 in 23). The survival time was significantly longer in the CIK group (41.9 months, 95% confidence interval [CI]: 38.2-45.7) than in the control group (33.8 months, 95% CI: 28.4-39.2). Although QOL was reduced in both treatment groups, adjuvant CIK cell transfusion significantly improved the QOL in patients with CRC. Toxicity was mild in patients with CIK treatment. CONCLUSIONS: Immunotherapy with CIK cells may serve as an adjuvant treatment in patients with CRC after CT with prolonged survival of patients, limited side-effects, and improved QOL.


Assuntos
Neoplasias Colorretais/genética , Células Matadoras Induzidas por Citocinas/metabolismo , Imunoterapia/métodos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Análise de Sobrevida
17.
Mol Med ; 23: 235-246, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28805233

RESUMO

Adoptive immunotherapy with Cytokine Induced Killer (CIK) cells has shown antitumor activity against several kinds of cancers in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T-NK phenotype and MHC-unrestricted antitumor activity. Literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (day 1, day 14 and day 21) of CIK cells expansion. Mature CIK cells (day 21) produce a great variety of interleukins and secreted proteins that can be divided into 3 groups based on their secretion quantity: high (IL-13, RANTES, MIP-1α and 1ß), medium (IL-1Ra, IL-5, IL-8, IL-10, IL-17, IP-10, INF-γ, VEGF and GMCSF) and low (IL-1ß, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, Eotaxin, PDGF-bb, FGF basic, G-CSF and MCP-1) secreted. Moreover, comparing PBMC (day 1) and mature CIK cells (day 14 and 21) secretome, we observed that IL-5, IL-10, IL-13, GM-CSF, VEGF resulted greatly up-regulated, while IL-1ß, IL-6, IL-8, IL-15, IL-17, eotaxin, MCP-1, and RANTES were down-regulated. We also performed a gene expression profile analysis of patient-derived CIK cells showing that mRNA for the different cytokines and secreted proteins were modulated during PBMC to CIK differentiation. We highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells. Our findings provide rationale to explore the functional implications and possible therapeutic modulation of CIK secretome.


Assuntos
Células Matadoras Induzidas por Citocinas/metabolismo , Citocinas/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Idoso , Proliferação de Células , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Pessoa de Meia-Idade , Transcriptoma
18.
Tumour Biol ; 39(3): 1010428317695961, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28349820

RESUMO

Recurrence of breast cancer after radiotherapy may be partly explained by the presence of radioresistant cells. Thus, it would be desirable to develop an effective therapy against radioresistant cells. In this study, we demonstrated the intense antitumor activity of cytokine-induced killer cells against MCF-7 and radioresistant MCF-7 cells, as revealed by cytokine-induced killer-mediated cytotoxicity, tumor cell proliferation, and tumor invasion. Radioresistant MCF-7 cells were more susceptible to cytokine-induced killer cell killing. The stronger cytotoxicity of cytokine-induced killer cells against radioresistant MCF-7 cells was dependent on the expression of major histocompatibility complex class I polypeptide-related sequence A/B on radioresistant MCF-7 cells after exposure of cytokine-induced killer cells to sensitized targets. In addition, we demonstrated that cytokine-induced killer cell treatment sensitized breast cancer cells to chemotherapy via the downregulation of TK1, TYMS, and MDR1. These results indicate that cytokine-induced killer cell treatment in combination with radiotherapy and/or chemotherapy may induce synergistic antitumor activities and represent a novel strategy for breast cancer.


Assuntos
Neoplasias da Mama/radioterapia , Terapia Baseada em Transplante de Células e Tecidos , Células Matadoras Induzidas por Citocinas/metabolismo , Recidiva Local de Neoplasia/radioterapia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Matadoras Induzidas por Citocinas/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos da radiação , Feminino , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Tolerância a Radiação , Timidina Quinase/biossíntese , Timidilato Sintase/biossíntese
19.
Immunol Lett ; 183: 37-43, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28143792

RESUMO

Dendritic cells (DCs) and cytokine-induced killer (CIK) cells have both shown activity as immunotherapy in some malignancies. Our aim was to prospective assess the effect of this immunotherapy in patients with stage IV breast cancer. Between Aug 2003 and Dec 2013, we collected 368 patients who met inclusion criteria and divided into immunotherapy group (treatment group: 188 patients) and chemotherapy group (control group: 180 patients). DCs were prepared from the mononuclear cells isolated from patients in the treatment group using IL-2/GM-CSF and were loaded with tumour antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. After the patients had received low-dose chemotherapy, those in the treatment group also received the DC-CIK therapy, which was repeated four times in a fortnight to form one cycle. At least three cycles of DC-CIK therapy were given. Immune function was measured in treatment group patients' sera. Disease-free survival (DFS) and Overall survival (OS) after the diagnosis of stage IV breast cancer was assessed after a 10-year follow-up. The result demonstrated that immune function is obviously enhanced after DC-CIK therapy. By Cox regression analysis, DC-CIK therapy reduced the risk of disease progression (p<0.01) with an increased OS (p<0.01). After low-dose chemotherapy, active immunization with DC-CIK immunotherapy is a potentially effective approach for the control of tumour growth in stage IV breast cancer patients.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Imunoterapia , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Vacinas Anticâncer/uso terapêutico , Terapia Combinada , Células Matadoras Induzidas por Citocinas/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
20.
Immunol Lett ; 181: 36-44, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27867030

RESUMO

Cytokine induced killer (CIK) cells have a powerful tumor cells killing activity both in vitro and in vivo and transfusion of these cells have become an adjuvant treatment for tumors. CIK cells are induced and amplified from peripheral blood mononuclear cells (PBMCs) with multiple cytokines. As CD4+CD25bri regulatory T cells can be also induced by high dose of interleukin 2 (IL-2) which is used for CIK cells amplification in the CIK cell culture system, the anti-tumor activity of CIK cells was suppressed to some extent. In order to overcome this unwanted suppressive factor, we found that low dose of gemcitabine could reduce the proportion of CD4+CD25bri regulatory T cells in the CIK cell culture system and significantly enhance the anti-tumor activity of CIK cells in vitro. The levels of interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) were also reduced significantly following the depletion of CD4+CD25bri regulatory T cells in gemcitabine treated CIK cell culture system. In vivo experiment showed that low dose of gemcitabine treated CIK cells significantly suppressed tumor growth and prolonged their lifespan in tumor-bearing nude mice, with the proportion of CD4+CD25bri regulatory T cells reduced. Meanwhile, we detected lower levels of IL-10, TGF-ß and a higher level of interferon-γ (IFN-γ) in tumor-bearing nude mice that received gemcitabine treated CIK cells transfusion than those in other groups. The possible mechanism involved in the enhanced anti-tumor activity in vivo was that gemcitabine treated CIK cells created a strengthened anti-tumor immune microenvironment with the changed levels of cytokines such as IL-10, TGF-ß and IFN-γ. These results suggested a strategy to improve the adoptive immune therapy in recent use by removing the suppressive factors and a more effective tumor treatment combining chemotherapy and immunotherapy.


Assuntos
Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Células Matadoras Induzidas por Citocinas/imunologia , Desoxicitidina/análogos & derivados , Imunomodulação/efeitos dos fármacos , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Matadoras Induzidas por Citocinas/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/farmacologia , Depleção Linfocítica , Masculino , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
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