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1.
Cancer Immunol Immunother ; 69(1): 135-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31807878

RESUMO

Development of personalized cancer vaccines based on neoantigens has become a new direction in cancer immunotherapy. Two forms of cancer vaccines have been widely studied: tumor-associated antigen (including proteins, peptides, or tumor lysates)-pulsed dendritic cell (DC) vaccines and protein- or peptide-adjuvant vaccines. However, different immune modalities may produce different therapeutic effects and immune responses when the same antigen is used. Therefore, it is necessary to choose a more effective neoantigen vaccination method. In this study, we compared the differences in immune and anti-tumor effects between neoantigen-pulsed DC vaccines and neoantigen-adjuvant vaccines using murine lung carcinoma (LL2) candidate neoantigens. The enzyme-linked immunospot (ELISPOT) assay showed that 4/6 of the neoantigen-adjuvant vaccines and 6/6 of the neoantigen-pulsed DC vaccines induced strong T-cell immune responses. Also, 2/6 of the neoantigen-adjuvant vaccines and 5/6 of the neoantigen-pulsed DC vaccines exhibited potent anti-tumor effects. The results indicated that the neoantigen-pulsed DC vaccines were superior to the neoantigen-adjuvant vaccines in both activating immune responses and inhibiting tumor growth. Our fundings provide an experimental basis for the selection of immune modalities for the use of neoantigens in individualized tumor immunotherapies.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral/transplante , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Modelos Animais de Doenças , Feminino , Humanos , Imunogenicidade da Vacina , Camundongos , Neoplasias/imunologia , Linfócitos T/imunologia
2.
Immunology ; 159(1): 75-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31587253

RESUMO

Dendritic cell (DC) -based cancer immunotherapy is one of the most important anti-cancer immunotherapies, and has been associated with variable efficiencies in different cancer types. It is well-known that tumor microenvironment plays a key role in the efficacy of various immunotherapies such as DC vaccine. Accordingly, the expression of programmed death ligand 1 (PD-L1) on DCs, which interacts with PD-1 on T cells, leads to inhibition of anti-tumor responses following presentation of tumor antigens by DCs to T cells. Therefore, we hypothesized that down-regulation of PD-L1 in DCs in association with silencing of PD-1 on T cells may lead to the enhancement of T-cell priming by DCs to have efficient anti-tumor T-cell responses. In this study, we silenced the expression of PD-L1 in DCs and programmed cell death protein 1 (PD-1) in T cells by small interfering RNA (siRNA) -loaded chitosan-dextran sulfate nanoparticles (NPs) and evaluated the DC phenotypic and functional characteristics and T-cell functions following tumor antigen recognition on DCs, ex vivo. Our results showed that synthesized NPs had good physicochemical characteristics (size 77·5 nm and zeta potential of 14·3) that were associated with efficient cellular uptake and target gene silencing. Moreover, PD-L1 silencing was associated with stimulatory characteristics of DCs. On the other hand, presentation of tumor antigens by PD-L1-negative DCs to PD-1-silenced T cells led to induction of potent T-cell responses. Our findings imply that PD-L1-silenced DCs can be considered as a potent immunotherapeutic approach in combination with PD-1-siRNA loaded NPs, however; further in vivo investigation is required in animal models.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Neoplasias do Colo/terapia , Células Dendríticas/transplante , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/imunologia , Terapêutica com RNAi , Linfócitos T/imunologia , Animais , Apoptose , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
3.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
4.
Immunology ; 158(4): 322-339, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509246

RESUMO

Current treatments for systemic autoimmune diseases partially improve the health of patients displaying low pharmacological efficacy and systemic immunosuppression. Here, the therapeutic potential of transferring tolerogenic dendritic cells (tolDCs) generated with heme-oxygenase inductor cobalt (III) protoporphyrin IX (CoPP), dexamethasone and rosiglitazone for the treatment of systemic autoimmunity was evaluated in two murine models of systemic lupus erythematosus (SLE), MRL-Faslpr and NZM2410 mice. Dendritic cells treated ex vivo with these drugs showed a stable tolerogenic profile after lipopolysaccharide stimulation. Regular doses of tolDCs were administered to anti-nuclear antibody-positive mice throughout 60-70 days, and the clinical score was evaluated. Long-term treatment with these tolDCs was well tolerated and effective to improve the clinical score on MRL-Faslpr lupus-prone mice. Additionally, decreased levels of anti-nuclear antibodies in NZM2410 mice were observed. Although tolDC treatment increased regulatory T cells, no significant reduction of renal damage or glomerulonephritis could be found. In conclusion, these results suggest that the transfer of histone-loaded tolDCs could improve only some SLE symptoms and reduced anti-nuclear antibodies. This is the first study to evaluate antigen-specific tolDC administration to treat SLE. Our report strengthens the clinical relevance of tolDC generation with CoPP, dexamethasone and rosiglitazone and the use of these modified cells as a therapy for systemic autoimmunity.


Assuntos
Células Dendríticas/imunologia , Imunoterapia Adotiva/métodos , Rim/patologia , Lúpus Eritematoso Sistêmico/terapia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Antinucleares/sangue , Diferenciação Celular , Células Cultivadas , Células Dendríticas/transplante , Dexametasona/metabolismo , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos MRL lpr , Pirazinas/metabolismo , Pirróis/metabolismo , Rosiglitazona/metabolismo
5.
Biomed Pharmacother ; 118: 109031, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545219

RESUMO

BACKGROUND: This study was conducted to investigate the protective effect of Fms-like tyrosine kinase 3 (FLT3)/FLT3 ligand (FLT3L)-dependent CD103+ dendritic cells (DCs) on hepatic ischemia-reperfusion injury (IRI). METHODS: A mouse model of hepatic IRI and cellular model following hypoxia-reperfusion (H/R) treatment were established. Peripheral blood and liver tissues were obtained and analyzed by flow cytometer in terms of percentage of CD103+DCs and regulatory T (Treg) cells. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were determined to assess liver function. Moreover, pro-inflammatory cytokines levels including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were measured using enzyme-linked immunosorbent assay (ELISA). The histological morphology of liver tissues was examined with hematoxylin and eosin (HE) staining. The apoptosis was detected by terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) assay. Treg-associated cytokines transforming growth factor (TGF)-ß and IL-10 expressions were measured using quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: CD103+ DCs were significantly decreased in peripheral blood and liver tissues of mouse model of hepatic IRI. In vivo experiments indicated that CD103+ DCs infusion ameliorated IRI-induced liver damage and Treg inhibition. Further investigations demonstrated that FLT3/FLT3L-dependent CD103+ DCs suppressed hepatocyte apoptosis via activation of Treg cells in vitro. CONCLUSION: FLT3/FLT3L-induced CD103+ DCs alleviated hepatic IRI through activating Treg cells.


Assuntos
Antígenos CD/metabolismo , Células Dendríticas/transplante , Cadeias alfa de Integrinas/metabolismo , Fígado/irrigação sanguínea , Proteínas de Membrana/metabolismo , Traumatismo por Reperfusão/terapia , Linfócitos T Reguladores/imunologia , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Transplante de Células , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fígado/imunologia , Testes de Função Hepática , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/imunologia
6.
World J Gastroenterol ; 25(29): 3941-3955, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31413529

RESUMO

BACKGROUND: Cholangiocarcinoma or biliary tract cancer has a high mortality rate resulting from late presentation and ineffective treatment strategy. Since immunotherapy by dendritic cells (DC) may be beneficial for cholangiocarcinoma treatment but their efficacy against cholangiocarcinoma was low. We suggest how such anti-tumor activity can be increased using cell lysates derived from an honokiol-treated cholangiocarcinoma cell line (KKU-213L5). AIM: To increase antitumour activity of DCs pulsed with cell lysates derived from honokiol-treated cholangiocarcinoma cell line (KKU-213L5). METHODS: The effect of honokiol, a phenolic compound isolated from Magnolia officinalis, on choangiocarcinoma cells was investigated in terms of the cytotoxicity and the expression of damage-associated molecular patterns (DAMPs). DCs were loaded with tumour cell lysates derived from honokiol-treated cholangiocarcinoma cells their efficacy including induction of T lymphocyte proliferation, proinflammatory cytokine production and cytotoxicity effect on target cholangiocarcinoma cells were evaluated. RESULTS: Honokiol can effectively activate cholangiocarcinoma apoptosis and increase the release of damage-associated molecular patterns. DCs loaded with cell lysates derived from honokiol-treated tumour cells enhanced priming and stimulated T lymphocyte proliferation and type I cytokine production. T lymphocytes stimulated with DCs pulsed with cell lysates of honokiol-treated tumour cells significantly increased specific killing of human cholangiocarcinoma cells compared to those associated with DCs pulsed with cell lysates of untreated cholangiocarcinoma cells. CONCLUSION: The present findings suggested that honokiol was able to enhance the immunogenicity of cholangiocarcinoma cells associated with increased effectiveness of DC-based vaccine formulation. Treatment of tumour cells with honokiol offers a promising approach as an ex vivo DC-based anticancer vaccine.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Compostos de Bifenilo/farmacologia , Vacinas Anticâncer/imunologia , Colangiocarcinoma/terapia , Imunoterapia/métodos , Lignanas/farmacologia , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Voluntários Saudáveis , Humanos , Imunogenicidade da Vacina , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Transplante Autólogo/métodos
7.
World J Gastroenterol ; 25(27): 3649-3663, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31367163

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells (DCs) and cytokine-induced killer cells (CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored. AIM: To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs, combined with different conventional treatments of HCC. METHODS: We performed a literature search on PubMed and Web of Science up to February 15, 2019. Long-term efficacy (overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis. RESULTS: A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio (RR) = 1.07; 95% confidence interval (CI): 1.01-1.13, P = 0.02], 1 year (RR = 1.12; 95%CI: 1.07-1.17, P < 0.00001), 3 years (RR = 1.23; 95%CI: 1.15-1.31, P < 0.00001) and 5 years (RR = 1.26; 95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo (RR = 0.50; 95%CI: 0.36-0.69, P < 0.0001) and 1 year (RR = 0.82; 95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe, feasible treatment. CONCLUSION: Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients' prognosis by increasing overall survival and reducing cancer recurrence.


Assuntos
Carcinoma Hepatocelular/terapia , Células Matadoras Induzidas por Citocinas/transplante , Células Dendríticas/transplante , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Ensaios Clínicos como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Estudos de Viabilidade , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/imunologia , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
8.
Cancer Immunol Immunother ; 68(9): 1467-1477, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451841

RESUMO

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Células Dendríticas/transplante , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Prospectivos , Piridinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Análise de Sobrevida
9.
J Immunol Res ; 2019: 1982570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355296

RESUMO

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-ß, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.


Assuntos
Artrite Experimental/terapia , Células Dendríticas/transplante , Tolerância Imunológica/imunologia , NF-kappa B/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Inflamação , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Masculino , Camundongos , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th17/imunologia
10.
Oncol Rep ; 42(1): 370-376, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115558

RESUMO

The present study aimed to investigate the antitumor effects of an intratumoral injection of dendritic cells (DCs) overexpressing interleukin-12 (IL­12) on melanoma. DCs, isolated from mouse spleen, were gene­modified using an IL­12 overexpression vector. Melanoma B6 cells were injected into C57BL/6 mice to generate tumors. Thereafter, DCs overexpressing IL­12 were injected into the tumors, and tumor volume was subsequently measured. Pathological changes in tumor tissue were detected by hematoxylin and eosin staining. The expression of interleukin-4 (IL­4) and IL­12 in tumors was measured by enzyme­linked immunosorbent assay, real­time PCR and western blotting. DCs were successfully isolated and a lentivirus vector expressing IL­12 was constructed. After intratumoral injection of phosphate­buffered saline (control group), tumor cells exhibited malignant growth; whereas tumors injected with DCs (DC group) or DCs + empty vector (DC + vector group) exhibited a small amount of inflammatory cell infiltration and limited areas of tissue necrosis. In contrast, tumors injected with DCs overexpressing IL­12 (DC + IL­12 group) displayed severe tissue necrosis, loss of cell structure, and inflammatory cell infiltration. Compared with the control group, the tumor volumes were significantly lower in the DC, the DC + vector and the DC + IL­12 groups, while the expression of IL­12 and IL­4 in the tumors was significantly higher. Importantly, the most marked changes in tumor volume and IL­12 and IL­4 expression were in the DC + IL­12 group, which were significantly greater than those in tumors treated with unmodified DCs. Hence, intratumoral injection of DCs overexpressing IL­12 exerted strong antitumor effects in melanoma, and biotherapy with DCs overexpressing IL­12 is a potential treatment strategy for melanoma.


Assuntos
Células Dendríticas/transplante , Interleucina-12/metabolismo , Lentivirus/fisiologia , Melanoma Experimental/terapia , Animais , Linhagem Celular Tumoral , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Injeções Intralesionais , Interleucina-12/genética , Interleucina-4/genética , Interleucina-4/metabolismo , Lentivirus/genética , Masculino , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Baço/citologia , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J BUON ; 24(2): 615-621, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128014

RESUMO

PURPOSE: To explore the therapeutic efficacy and safety of the combination treatment of dendritic cells and cytokine-induced killers (DC-CIK) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients diagnosed with advanced HCC and treated with DC-CIK and/or sorafenib in the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University from January 2015 to January 2016 were retrospectively analyzed. HCC patients were divided into (A): control group (oral administration of sorafenib) and (B): observation group (oral administration of sorafenib combined with DC-CIK). Patients were followed up every 4-8 weeks. Overall survival and adverse events of each patient were recorded. Therapeutic efficacy was evaluated using the modified RECIST criteria. RESULTS: After treatment, ALT and TBIL were remarkably elevated in the control group and decreased in the observation group. No significant change in AFP level was seen in the control group after treatment, whereas it was remarkably decreased in the observation group. The efficacy rate was 16.7% and 51.4% in the control and observation group, respectively. Clinical benefit rate (CBR) was 41.9% and 88.6% in the control group and observation group, respectively. The median survival time of the control and observation group was 13.8 and 18.6 months, respectively. In the observation group there was a significant difference in the survival time between patients with Child-Pugh A and Child-Pugh B, respectively. CONCLUSIONS: DC-CIK combined with sorafenib could improve the tumor response rate and prolong overall survival of advanced HCC without increasing the incidence of adverse events. HCC patients achieve a more stable disease condition and longer overall survival with DC-CIK combined with sorafenib than those with individual sorafenib treatment.


Assuntos
Carcinoma Hepatocelular/terapia , Células Matadoras Induzidas por Citocinas/transplante , Neoplasias Hepáticas/terapia , Sorafenibe/administração & dosagem , Idoso , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Combinada , Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Humanos , Imunoterapia Adotiva , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Sorafenibe/efeitos adversos , Resultado do Tratamento
12.
Immunol Invest ; 48(8): 794-808, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31094258

RESUMO

Stimulating antitumor T cells using dendritic cells (DCs) is a novel and promising method in cancer therapy. Poly lactic-co-glycolic acid is one of the best-known polymers used for encapsulating antigen to protect them against proteolytic enzymes. In this study, poly lactic-co-glycolic acid nanoparticles (NPs) were used as DC antigen delivery vehicles in a preclinical model of immunotherapy of gastric cancer. The DCs were generated from peripheral blood monocytes by conventional in vitro differentiation and loaded with either soluble tumor lysate or lysate encapsulated in NPs using a double emulsion/solvent evaporation technique. Morphology of NPs was determined by scanning electron microscopy. Tumor lysate, either in the soluble form or encapsulated in NPs, was loaded into DC and stimulatory capacity was compared using patient-derived autologous CD3+ T cells as responders. The amount of relevant cytokines produced by Ag-loaded DC and in DC/T cell cocultures was evaluated as a measure of initial DC stimulation and T-cell responses, respectively. Significance increases in expression of DC surface molecules (i.e., CD80, CD83, CD86, and Human Leukocyte Antigen-DR (HLA-DR)) and cytokine production by both DC and DC/T cell cocultures (i.e., interleukin (IL)-12:IL-10 and interferon [IFN]-γ:IL-4 ratios) was observed following loading with lysate NP versus controls. The results suggest that NP-encapsulated antigen can shift antitumor T-cell responses toward a Th1 bias, which potentially increases DC vaccine potency in clinical settings.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Imunoterapia/métodos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Neoplasias Gástricas/terapia , Antígenos de Neoplasias/química , Antígenos de Superfície/imunologia , Antígenos de Superfície/metabolismo , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Microscopia Eletrônica de Varredura , Nanopartículas/ultraestrutura , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
13.
Int J Rheum Dis ; 22(7): 1255-1262, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062502

RESUMO

AIM: Cumulative evidence has revealed that tolerogenic dendritic cells (tolDC) could relieve inflammation reactions in various autoimmune diseases. This study investigated the potential therapeutic application of vasoactive intestinal peptide (VIP)-induced tolDC (VIP-DC) on arthritis using collagen-induced arthritis (CIA) mice. METHODS: Bone marrow cells were differentiated into dendritic cells (DC) using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4. tolDC were induced by either VIP or Bay 11-7082 in vitro. Immunophenotypes and cytokine production of VIP-DC and Bay-DC were detected by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay, respectively. Bay-DC, VIP-DC and untreated DC were ip administrated to CIA mice on day 40 when arthritis was onset. The treatment effects on arthritic and pathological changes, including synovial hyperplasia, pannus formation, inflammation and bone erosion, were assessed. RESULTS: VIP-DC (40 ng/mL) and Bay-DC (0.5 µg/mL) had a lower level of major histocompatibility complex II, CD40 and CD86 expression, reduced γ-interferon and increased IL-4 production (P < 0.05 or 0.01), compared with untreated DC. The administration of VIP-DC and Bay-DC decreased the arthritis score clinically at the end of the therapy. Pathological assessments showed that bone erosion and inflammation were alleviated in the VIP-DC group compared with those in the untreated DC group (P < 0.05 and P < 0.01, respectively). CONCLUSION: VIP-DC showed reduced immunogenicity and enhanced anti-inflammatory cytokine production. Both VIP-DC and Bay-DC could ameliorate arthritis in CIA mice clinically. VIP-DC were not inferior to Bay 11-7082-induced tolDC but may exert a better preventive effect on bone destruction.


Assuntos
Artrite Experimental/prevenção & controle , Colágeno , Células Dendríticas/transplante , Tolerância Imunológica , Articulações/imunologia , Peptídeo Intestinal Vasoativo/imunologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/metabolismo , Interleucina-4/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA , Fenótipo
15.
Trials ; 20(1): 242, 2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029154

RESUMO

BACKGROUND: Pancreatic cancer is a refractory malignancy, and the development of a new effective treatment strategy is needed. We generated a dendritic cell vaccine by culturing monocytes obtained by apheresis of blood from each patient, inducing their differentiation into dendritic cells, and pulsing with tumor antigen peptides. However, the clinical efficacy of the vaccine has not been established. We therefore decided to conduct an exploratory clinical trial of dendritic cell vaccine loaded with Wilms' tumor gene 1 peptides (TLP0-001) as a potential new treatment for patients with advanced pancreatic cancer refractory to standard chemotherapy. METHODS: This is an investigator-initiated, double-blind, comparative trial. The patients were allocated to two groups in a 1:1 ratio through a central registration by dynamic allocation. A total of 185 patients with inoperable or metastatic pancreatic cancer who were refractory or intolerant to standard primary chemotherapy with gemcitabine plus nab-paclitaxel will be allocated to secondary treatment either with placebo in combination with S-1 (the control group) or TLP0-001 in combination with S-1 (the investigational product group). The primary objective of this trial is to evaluate the safety and efficacy (as measured by overall survival) of the investigational product by comparing the two groups. This clinical trial will be performed in accordance with Japanese Good Clinical Practice guidelines. DISCUSSION: Clinical trials of the standard regimen, including gemcitabine, for advanced pancreatic cancer are ongoing worldwide. However, a strategy for after the primary treatment has not been established. We therefore decided to conduct this study to evaluate the safety and efficacy of TLP0-001 as a secondary treatment for pancreatic cancer in anticipation of the approval of this new drug in Japan. This trial is conducted with full consideration of safety, as it is the first-in-human clinical trial of TLP0-001; thus, the trial will be conducted only at the Second Department of Surgery at Wakayama Medical University until the safety is confirmed by interim analysis. We plan to conduct a multicenter trial at 18 institutions in Japan after confirmation of the safety. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000027179 . Registered on 9 April 2017.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Células Dendríticas/transplante , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/terapia , Fragmentos de Peptídeos/imunologia , Tegafur/uso terapêutico , Proteínas WT1/imunologia , Adulto , Idoso , Vacinas Anticâncer/efeitos adversos , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Células Dendríticas/imunologia , Método Duplo-Cego , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tegafur/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
PLoS One ; 14(3): e0212911, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30822345

RESUMO

In recent years a non-neuronal cholinergic system has been described in immune cells, which is often usually activated during the course of inflammatory processes. To date, it is known that Acetylcholine (ACh), a neurotransmitter extensively expressed in the airways, not only induces bronchoconstriction, but also promotes a set of changes usually associated with the induction of allergic/Th2 responses. We have previously demonstrated that ACh polarizes human dendritic cells (DC) toward a Th2-promoting profile through the activation of muscarinic acetylcholine receptors (mAChR). Here, we showed that ACh promotes the acquisition of an inflammatory profile by murine DC, with the increased MHC II IAd expression and production of two cytokines strongly associated with inflammatory infiltrate and tissue damage, namely TNF-α and MCP-1, which was prevented by blocking mAChR. Moreover, we showed that ACh induces the up-regulation of M3 mAChR expression and the blocking of this receptor with tiotropium bromide prevents the increase of MHC II IAd expression and TNF-α production induced by ACh on DC, suggesting that M3 is the main receptor involved in ACh-induced activation of DC. Then, using a short-term experimental murine model of ovalbumin-induced lung inflammation, we revealed that the intranasal administration of ACh-treated DC, at early stages of the inflammatory response, might be able to exacerbate the recruitment of inflammatory mononuclear cells, promoting profound structural changes in the lung parenchyma characteristic of chronic inflammation and evidenced by elevated systemic levels of inflammatory marker, TNF-α. These results suggest a potential role for ACh in the modulation of immune mechanisms underlying pulmonary inflammatory processes.


Assuntos
Acetilcolina/metabolismo , Células Dendríticas/imunologia , Lesão Pulmonar/imunologia , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Modelos Animais de Doenças , Progressão da Doença , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/sangue , Lesão Pulmonar/diagnóstico , Camundongos , Ovalbumina/imunologia , Cultura Primária de Células , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
17.
Rev Mal Respir ; 36(3): 415-425, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30902445

RESUMO

Antigen-specific immunotherapy also known as cancer vaccination offers a novel approach for the treatment of non-small cell lung cancer patients. It relies on specific priming of the immune system in order to provoke or increase adaptive antitumor immune response against the vaccine component. Several molecules have been developed in lung cancer, based on whole-tumor cells, dendritic cells, peptides, recombinant proteins, or viral vectors. The aim of this review is to describe the mechanism of action of these vaccines and the results of the main clinical studies.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Desenvolvimento de Medicamentos/tendências , Humanos , Imunoterapia/tendências , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/fisiologia
18.
Int Immunopharmacol ; 70: 378-386, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852293

RESUMO

BACKGROUND: Therapeutic potential of helminth have been shown to have a protective effect on immune-mediated diseases such as Crohn's disease (CD), which is associated with increased production of T helper cell type 1. However, helminth therapy is unacceptable to patients due to side-effects and the fear of parasites. As helminths regulate the cellular immune responses through innate cells such as dendritic cells (DCs), cellular immunotherapy has been considered a therapeutic option to treat CD. METHODS: Bone marrow-dendritic cells were generated, enriched and treated with Trichinella spiralis muscle larval excretory/secretory products (Ts-MLES). DCs maturation was measured by flow cytometry and cytokine production of DCs were measured by ELISA. Colitis was generated by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) solution. For adoptive transfer, Ts-MLES treated-DCs injected intravenously 24 h prior to TNBS challenge. Disease activity index (DAI) including weight loss, diarrhea, and bloody stool were measured. Colon segments were stained with hematoxylin and eosin (H.E.) and periodic acid schiff (PAS) staining for histological damage scoring. The relative mRNA expression of cytokines in colon was analyzed by RT-PCR. Cytokine production in colon was measured by ELISA. Splenocytes were separated and cytokine profiles including Th1 (IFN-γ), Th2 (IL-4, IL-13), and Treg subsets (IL-10, TGF-ß) were analyzed by flow cytometry. RESULTS: Ts-MLES regulated the maturation and cytokine production of DCs. Ts-MLES -DC ameliorated the severity of the TNBS-induced colitis. In the colon and the spleen, Ts-MLES-DC decreased IFN-γ (Th1) significantly and increased Th2 (IL-4, IL-13)- and Treg (IL-10, TGF-ß)- related cytokines. CONCLUSIONS: Ts-MLES-DC ameliorated the severity of the TNBS-induced colitis through decreasing IFN-γ. Ts-MLES-DC skewed the Th1-mediated response toward the Th2 type and regulatory T cell response.


Assuntos
Antígenos de Helmintos/metabolismo , Colite/terapia , Células Dendríticas/imunologia , Proteínas de Helminto/metabolismo , Imunoterapia/métodos , Doenças Inflamatórias Intestinais/terapia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Trichinella spiralis/fisiologia , Animais , Colite/induzido quimicamente , Citocinas/metabolismo , Células Dendríticas/transplante , Modelos Animais de Doenças , Feminino , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Terapia com Helmintos , Ácido Trinitrobenzenossulfônico
20.
Front Immunol ; 10: 79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804929

RESUMO

Diabetes mellitus is characterized by long standing hyperglycemia leading to numerous life-threatening complications. For type 1 diabetes mellitus, resulting from selective destruction of insulin producing cells by exaggerated immune reaction, the only effective therapy remains exogenous insulin administration. Despite accurate compliance to treatment of certain patients, transient episodes of hyperglycemia cannot be completely eliminated by this symptomatic treatment. Novel immunotherapeutic approaches based on tolerogenic dendritic cells, T regulatory cells and mesenchymal stem cells (MSCs) have been tested in clinical trials, endeavoring to directly modulate the autoimmune destruction process in pancreas. However, hyperglycemia itself affects the immune system and the final efficacy of cell-based immunotherapies could be affected by the different glycemic control of enrolled patients. The present review explores the impact of hyperglycemia on immune cells while providing greater insight into the molecular mechanisms of high glucose action and subsequent metabolic reprogramming of different immune cells. Furthermore, over-production of mitochondrial reactive oxygen species, formation of advanced glycation end products as a consequence of hyperglycemia and their downstream signalization in immune cells are also discussed. Since hyperglycemia in patients with type 1 diabetes mellitus might have an impact on immune-interventional treatment, the maintenance of a tight glucose control seems to be beneficial in patients considered for cell-based therapy.


Assuntos
Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Hiperglicemia/imunologia , Imunoterapia Adotiva/métodos , Células-Tronco Mesenquimais/imunologia , Mitocôndrias/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Reprogramação Celular , Ensaios Clínicos como Assunto , Células Dendríticas/imunologia , Células Dendríticas/transplante , Humanos , Tolerância Imunológica/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Monitorização Fisiológica , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Reguladores/transplante
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