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1.
Biomed Pharmacother ; 133: 110921, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378991

RESUMO

Dendritic cells (DCs) play a critical immuno-modulating role in pregnancy, which requires the maternal immune system to tolerate semiallogeneic fetus and at the same time to maintain adequate defense against pathogens. DCs interact closely with other immune components such as T cells, natural killer cells and macrophages, as well as the endocrine system to keep a pregnancy-friendly environment. Aberrant DC activities have been related to various pregnancy-associated diseases such as recurrent spontaneous abortion, preterm birth, pre-eclampsia, peripartum cardiomyopathy and infectious pregnancy complications. These findings make DCs an attractive candidate for prevention or therapy on the pregnancy-associated diseases. Here, we review recent findings that provide new insights into the roles of DCs in pregnancy and the related diseases. We also discuss the medical potentials to manipulate DCs in clinics. Whereas this is an emerging area with much work remaining, we anticipate that a better understanding of the role of DCs in maternal-fetal immunotolerance and a therapeutic manipulation of DCs will help women suffering from the pregnancy-associated diseases.


Assuntos
Células Dendríticas/imunologia , Histocompatibilidade Materno-Fetal , Tolerância Imunológica , Troca Materno-Fetal/imunologia , Complicações na Gravidez/imunologia , Transferência Adotiva , Animais , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Feminino , Terapia Genética , Histocompatibilidade Materno-Fetal/genética , Humanos , Tolerância Imunológica/genética , Troca Materno-Fetal/genética , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Complicações na Gravidez/prevenção & controle , Fatores de Risco , Transdução de Sinais
2.
Methods Mol Biol ; 2193: 159-174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32808268

RESUMO

Plasmacytoid dendritic cells (pDCs) are crucial for corneal homeostasis through secretion of various anti-angiogenic molecules and growth factors. Due to its avascular nature, only a limited number of adoptively transferred cells home to the cornea, when administered systemically. In addition, local adoptive transfer of cells poses several challenges and the clinical application of commonly used techniques is limited. Herein, we detail a novel approach for local adoptive transfer of pDCs to the cornea for the treatment of corneal wounds. This approach utilizes a commonly used fibrin sealant as a means of transferring previously isolated cells locally on the cornea. The technique is simple, reproducible, and is accompanied with successful transfer and integration of a substantial number of the cells to the cornea. Application of this approach to transfer pDCs promotes corneal wound healing. Furthermore, this technique can be applied for adoptive transfer of any cell of interest to the cornea.


Assuntos
Transferência Adotiva/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Dendríticas/transplante , Imunoterapia Adotiva/métodos , Cicatrização , Animais , Córnea/crescimento & desenvolvimento , Córnea/patologia , Lesões da Córnea/patologia , Lesões da Córnea/terapia , Epitélio Anterior/crescimento & desenvolvimento , Epitélio Anterior/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL
3.
Nat Commun ; 11(1): 5173, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057068

RESUMO

In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/transplante , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/terapia , Células Th17/imunologia , Idoso , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Feminino , Receptor 1 de Folato/imunologia , Humanos , Imunidade Humoral , Injeções Intradérmicas , Interferon gama/metabolismo , Interleucina-17/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Células Th17/metabolismo , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos
4.
Cancer Immunol Immunother ; 69(11): 2393-2401, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32535637

RESUMO

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS: The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. RESULTS: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.


Assuntos
Antineoplásicos/uso terapêutico , Células Dendríticas/transplante , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/terapia , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo
5.
Iran J Immunol ; 17(1): 14-25, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32224538

RESUMO

BACKGROUND: Melanoma is a common and malignant cutaneous tumor, which is responsible for a large proportion of skin cancer deaths. Dendritic cell (DC)-based vaccines have achieved positive results in the treatment of melanoma because of their ability to induce cytotoxic response to facilitate tumor elimination. OBJECTIVE: To improve the efficacy of dendritic cell-based vaccines by the adjuvant activity of Helicobacter pylori neutrophil activating protein (HP-NAP). METHODS: The recombinant HP-NAP (rHP-NAP) was expressed by using prokaryotic expression system. DCs were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. After treating with rHP-NAP, the maturation of DCs and dendritic cell-based vaccine were assayed by using flow cytometry and qRT-PCR. The activation and proliferation of T cells were measured by FCM, ELISA and MTT methods. The tumor specific cytotoxic response to resistant B16F10 was detected by using lactate dehydrogenase-release assay and qRT-PCR. RESULTS: The rHP-NAP, prepared from E. coli prokaryotic expression system, was able to significantly promote the maturation of dendritic cell-based vaccine loaded with tumor cell lysate (TCL) of B16F10 (DC-B16F10-TCL). Furthermore, it effectively induced the activation and proliferation of T cells and tumor specific cytotoxic response to resistant B16F10 melanoma tumor cells. CONCLUSION: These results suggested that rHP-NAP possesses the potential for use as an adjuvant of dendritic cell-based vaccine in anti-melanoma treatment.


Assuntos
Adjuvantes Imunológicos/farmacologia , Proteínas de Bactérias/farmacologia , Vacinas Anticâncer/farmacologia , Células Dendríticas/transplante , Melanoma Experimental , Animais , Proteínas de Bactérias/imunologia , Vacinas Anticâncer/imunologia , Humanos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Receptores Toll-Like/agonistas
6.
J Clin Neurosci ; 74: 187-193, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32169363

RESUMO

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Carmustina/uso terapêutico , Ácidos Decanoicos/uso terapêutico , Células Dendríticas/transplante , Glioma/terapia , Poliésteres/uso terapêutico , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Antineoplásicos/uso terapêutico , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinação/métodos
7.
Sci Rep ; 10(1): 5134, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198428

RESUMO

Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on the HIV reservoir. HIV+, stably treated participants in whom resting CD4+ T cell-associated HIV RNA (rca-RNA) increased after VOR exposure ex vivo and in vivo received 4 doses of AGS-004 every 3 weeks, followed by VOR every 72 hours for 30 days, and then the cycle repeated. Change in VOR-responsive host gene expression, HIV-specific T cell responses, low-level HIV viremia, rca-RNA, and the frequency of resting CD4+ T-cell infection (RCI) was measured at baseline and after each cycle. No serious treatment-related adverse events were observed among five participants. As predicted, VOR-responsive host genes responded uniformly to VOR dosing. Following cycles of AGS-004 and VOR, rca-RNA decreased significantly in only two participants, with a significant decrease in SCA observed in one of these participants. However, unlike other cohorts dosed with AGS-004, no uniform increase in HIV-specific immune responses following vaccination was observed. Finally, no reproducible decline of RCI, defined as a decrease of >50%, was observed. AGS-004 and VOR were safe and well-tolerated, but no substantial impact on RCI was measured. In contrast to previous clinical data, AGS-004 did not induce HIV-specific immune responses greater than those measured at baseline. More efficacious antiviral immune interventions, perhaps paired with more effective latency reversal, must be developed to clear persistent HIV infection.


Assuntos
Células Dendríticas/transplante , Infecções por HIV/terapia , HIV-1/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Imunoterapia Adotiva/métodos , Vorinostat/uso terapêutico , Adulto , Linfócitos T CD4-Positivos/imunologia , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia , Pesquisa Médica Translacional , Resultado do Tratamento , Vacinação
8.
Cell Immunol ; 349: 104049, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057353

RESUMO

Pathogenic microorganisms utilize multiple approaches to break down host immunity in favor of their invasion, of which, cystatin C is one of the soluble factors secreted by parasites reported to affect host immunity in vivo. The cellular targets and mechanisms of action in vivo of cystatin C, however, are far from clear. As professional antigen-presenting cells, dendritic cells (DCs) are first immune cells that contact foreign pathogenic agents or their products to initiate immune responses. We previously reported that cystatin C can regulate the functions of DCs in terms of suppressed CD4+ T cell activation but enhanced Th1/Th17 differentiation via different mechanisms. Here, we further verified these regulatory effects of cystatin C on DCs in vivo. We found that the suppressive role of DC-mediated CD4+ T cell proliferation by cystatin C was partly cell-contact independent and extended to CD8+ T cells in vivo. Although cystatin C-overexpressing DCs trafficked equally as their mock-transduced counterparts, their adoptive transfer suppressed CD8+ T cell immunity and resulted in compromised tumor rejection in both vaccination and treatment regimes. Compared with their role in promoting Th17 differentiation in vivo, cystatin C-transduced DCs had far greater ability to induce T regulatory cells (Tregs), leading to collectively a higher Treg/Th17 ratio in an adoptively transferred disease model, and thus relieved Th17-dependent autoimmunity. Collectively, these data demonstrated strong in vivo evidences for immune regulatory roles of cystatin C in DCs and provided theoretical basis for the application of cystatin C-transduced cell therapy in the treatment or remission of certain autoimmune diseases. (246).


Assuntos
Transferência Adotiva , Artrite Experimental/terapia , Doenças Autoimunes/terapia , Cistatina C/fisiologia , Células Dendríticas/imunologia , Evasão Tumoral/imunologia , Transferência Adotiva/efeitos adversos , Animais , Comunicação Celular , Células Cultivadas , Cistatina C/genética , Células Dendríticas/transplante , Regulação para Baixo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Granzimas/biossíntese , Granzimas/genética , Imunoterapia Adotiva , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Ovalbumina/imunologia , Proteínas Citotóxicas Formadoras de Poros/biossíntese , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Recombinantes/metabolismo , Organismos Livres de Patógenos Específicos , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Transdução Genética
9.
Cytotherapy ; 22(1): 6-15, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32005355

RESUMO

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths with high recurrence after surgery due to a paucity of effective post-surgical adjuvant treatments. DC vaccines can activate multiple anti-tumor immune responses but have not been explored for post-surgery PDAC recurrence. Intraperitoneal (IP) delivery may allow increased DC vaccine dosage and migration to lymph nodes. Here, we investigated the role of prophylactic DC vaccination controlling PDAC tumor growth with IP delivery as an administration route for DC vaccination. METHODS: DC vaccines were generated using ex vivo differentiation and maturation of bone marrow-derived precursors. Twenty mice were divided into four groups (n = 5) and treated with DC vaccines, unpulsed mature DCs, Panc02 lysates or no treatment. After tumor induction, mice underwent three magnetic resonance imaging scans to track tumor growth. Apparent diffusion coefficient (ADC), a quantitative magnetic resonance imaging measurement of tumor microstructure, was calculated. Survival was tracked. Tumor tissue was collected after death and stained with hematoxylin and eosin, Masson's trichrome, terminal deoxynucleotidyl transferase dUTP nick end labeling and anti-CD8 stains for histology. RESULTS: DC-vaccinated mice demonstrated stronger anti-tumor cytotoxicity compared with control groups on lactate dehydrogenase assay. DC vaccine mice also demonstrated decreased tumor volume, prolonged survival and increased ΔADC compared with control groups. On histology, the DC vaccine group had increased apoptosis, increased CD8+ T cells and decreased collagen. ΔADC negatively correlated with % collagen in tumor tissues. DISCUSSION: Prophylactic DC vaccination may inhibit PDAC tumor growth during recurrence and prolong survival. ΔADC may be a potential imaging biomarker that correlates with tumor histological features.


Assuntos
Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/terapia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Neoplasias Pancreáticas/terapia , Adenocarcinoma/terapia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/prevenção & controle , Vacinação
10.
Eur J Immunol ; 50(5): 725-735, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32012249

RESUMO

Extracorporeal photochemotherapy (ECP) that takes advantage of the immunomodulatory effects of UV light has been extensively used for many years for the treatment of several T cell-mediated diseases, including graft-versus-host disease (GvHD) and systemic scleroderma. Immune mechanisms that lead to the establishment of T cell tolerance in ECP-treated patients remain poorly known. In this study, we have tested the effect of UV/psoralen-treated BM-derived dendritic cells, referred to as ECP-BMDCs on the outcome of an antigen-specific T cell-mediated reaction, that is, contact hypersensitivity (CHS), which is mediated by CD8+ effector T cells (CD8+ Teff ). The intravenous (i.v.) injection of antigen-pulsed ECP-BMDCs in recipient C57BL/6 mice induced specific CD8+ T cells endowed with immunomodulatory properties (referred to as CD8+ TECP ), which prevented the priming of CD8+ Teff and the development of CHS, independently of conventional CD4+ regulatory T cells. CD8+ TECP mediated tolerance by inhibiting the migration and functions of skin DC and subsequently the priming of CD8+ Teff . CD8+ TECP displayed none of the phenotypes of the usual CD8+ T regulatory cells described so far. Our results reveal an underestimated participation of CD8+ T cells to ECP-induced immunomodulation that could explain the therapeutic effects of ECP in T cell-mediated diseases.


Assuntos
Células Dendríticas/imunologia , Dermatite de Contato/terapia , Tolerância Imunológica , Imunomodulação/efeitos da radiação , Linfócitos T Citotóxicos/efeitos da radiação , Linfócitos T Reguladores/efeitos da radiação , Alérgenos/administração & dosagem , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células Dendríticas/citologia , Células Dendríticas/transplante , Dermatite de Contato/imunologia , Dermatite de Contato/fisiopatologia , Dinitrofluorbenzeno/administração & dosagem , Modelos Animais de Doenças , Feminino , Ficusina/administração & dosagem , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fotoferese/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Raios Ultravioleta
11.
Cytotherapy ; 22(1): 35-43, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31902660

RESUMO

BACKGROUND: Clinical studies have shown the efficacy of combination therapy for various malignancies. In this study, the characteristics, safety and feasibility of use of cascade-primed (CAPRI) cells for the combination treatment of non-small-cell lung cancer (NSCLC) were evaluated both in vitro and in vivo. METHODS: Sixty-five patients with stage II-IV NSCLC were recruited. Of these patients, 31 patients received CAPRI cell therapy combined with chemotherapy (CAPRI group), and the other 34 patients constituted the control group and received chemotherapy alone. This study primarily aimed to evaluate the overall survival (OS), progression-free survival (PFS), short-term responses and treatment efficacy. RESULTS: CD83, CD1a, CD80 and CD86 marker levels were significantly upregulated in CAPRI cells. Interferon-γ expression levels were highest in CD3+CD8+ cells (33.77% ± 4.40%). Furthermore, interleukin-2 levels were highest in CD3+CD56+ cells (26.73% ± 6.63%), whereas perforin expression levels were similar in CD3+CD8+ and CD3+CD56+ cells. Furthermore, CAPRI cells had a better anti-tumor potential in CD3+CD56+ cells and displayed the highest expression levels of CD107a to H460 and A549 cell lines. The 5-year OS was significantly greater in the CAPRI group than in the control group (P = 0.008), and the PFS of two groups exhibited a significant difference (P = 0.007). Median OS (48 versus 31.6 months; P = 0.004) and PFS (48 versus 36.4 months; P = 0.016) differed between these two groups. Moreover, treatment-associated toxicities were mild and well-tolerated by patients with NSCLC. CONCLUSION: CAPRI cell therapy potentially prolongs the survival of patients with NSCLC when combined with chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Adjuvantes Imunológicos/uso terapêutico , Adulto , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Combinada , Células Dendríticas/transplante , Feminino , Seguimentos , Humanos , Interleucina-2/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/transplante , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
12.
Oncol Rep ; 43(2): 671-680, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894312

RESUMO

Breast cancer is the most common oncological pathology in women worldwide. Techniques for improving the clinical parameters of patients undergoing combination therapy for breast cancer are currently under development. A type of treatment employing dendritic cells (DCs) and cytotoxic DC­induced antigen­specific T lymphocytes efficiently eliminates residual cancer cells that are the key cause of tumor recurrence and metastasis. In the present study, DCs and activated lymphocytes (treated with IL­12 and IL­18) were isolated from the peripheral blood of patients with breast cancer, using a lysate of tumor tissue as antigen. The patients received the cells as part of adjuvant or neoadjuvant regimens (stage IV disease or progression). Evaluation of immunity was performed at 3 and 6 months after terminating immunotherapy. Evaluation of the disease­free period was performed for 3 years after surgery. The use of antigen­loaded autologous DCs combined with mononuclear cells with increased cytotoxic activity following Th1 polarization reduced the populations of immunosuppressive cells. The results of the present study demonstrated that the investigated cellular immunotherapy for breast cancer is safe, reduces the risk of relapse and metastasis, and improves immunity by reducing the number of regulatory T cells. Therefore, this therapeutic strategy may represent a novel approach to combating distant metastases of breast cancer.


Assuntos
Neoplasias da Mama/terapia , Células Dendríticas/transplante , Interleucina-12/imunologia , Interleucina-18/imunologia , Linfócitos T Citotóxicos/transplante , Adulto , Idoso , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Terapia Combinada , Células Dendríticas/imunologia , Feminino , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Transplante Autólogo , Resultado do Tratamento
13.
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
14.
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
15.
Iran J Immunol ; 16(4): 268-277, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885004

RESUMO

BACKGROUND: Dendritic cells (DCs) contribute essentially to the outset and course of immune responses. So in patients with malignancy, there have been considerable interests in use of these cells in different interventions. OBJECTIVE: To evaluate the impact of Leishmania major's components on DC maturation and their use as a therapeutic agent against tumor cells. METHODS: The cancer model was induced by injection of WEHI-164 cells (BALB/c derived fibrosarcoma cell line) subcutaneously in the right flank of animals. Bone-marrow derived DCs (BMDCs) were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. After 5 days, tumor lysate, Leishmania major's lysate, and Lipopolysaccharide (LPS) were added to the culture and incubated for 2 days. IL-12 production in DCs was measured by ELISA. For Immunotherapy, Mice received DCs subcutaneously around the tumor site. Two weeks after DCs injection, cytotoxicity assay and infiltration of CD8+ lymphocytes were evaluated. RESULTS: Our results showed that immunotherapy with dendritic cells exposed to Leishmania extract led to producing a higher amount of IL-12, compare to the control group. A considerable increment in specific cytotoxic T cells activity, diminished tumor growth rate and improved survival of immunized animals were seen. CONCLUSION: This study indicates that the use of Leishmania major extract, as well as LPS, can enhance the efficiency of DC-based vaccines and provides a basis for the use of Leishmania major in DC-targeted clinical therapies.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas , Imunidade Celular , Leishmania major/imunologia , Neoplasias Experimentais , Linfócitos T , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Fibrossarcoma/imunologia , Fibrossarcoma/patologia , Fibrossarcoma/terapia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Linfócitos T/imunologia , Linfócitos T/patologia
16.
Pathol Res Pract ; 215(12): 152691, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31676092

RESUMO

Despite significant advances over the past decades of research, pancreatic cancer (PC) continues to have the worst 5-year survival of any malignancy. Dendritic cells (DCs) are the most potent professional antigen-presenting cells and are involved in the induction and regulation of antitumor immune responses. DC-based immunotherapy has been used in clinical trials for PC. Although safety, efficacy, and immune activation were reported in patients with PC, DC vaccines have not yet fulfilled their promise. Additional strategies for combinatorial approaches aimed to augment and sustain the antitumor specific immune response elicited by DC vaccines are currently being investigated. Here, we will discuss DC vaccination immunotherapies that are currently under preclinical and clinical investigation and potential combination approaches for treating and improving the survival of PC patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Imunoterapia Adotiva , Neoplasias Pancreáticas/terapia , Animais , Antineoplásicos Imunológicos/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Quimioterapia Adjuvante , Células Dendríticas/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Evasão Tumoral
17.
Sci Rep ; 9(1): 15527, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664180

RESUMO

The graft-versus-leukemia effect reminds us to observe the allogeneic cell elicited anti-tumor immune responses. Here we immunized recipient B6 mice with different types of allogenic leukocytes and found that vaccination with allogenic dendritic cells (alloDC) elicited the most efficient protection against broad-spectrum tumors. The recipient lymphocytes were analyzed and the data showed that CD8 T cells increased significantly after immunization and expressed effector memory T cell marker KLRG1. Functional evaluation demonstrated that these KLRG1+CD8 T cells could kill tumor cells in vitro and in vivo in Granzyme B- and Fas/FasL-dependent manners with no tumor antigen specificity, and tend to migrate into tumor sites by high expression of heparanase. Adoptive transfer of these cells could provide antitumor protection against tumors. AlloDC could also treat mice with residual tumors and combination of anti-PD1 antibody could enhance this effects. Together, our study showed that alloDC-immunization could induce potent antitumor effect through the expansion of KLRG1+CD8 T cells, which can work as both preventive and therapeutic tumor vaccines.


Assuntos
Transferência Adotiva , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas , Imunidade Celular , Lectinas Tipo C/imunologia , Neoplasias Experimentais/imunologia , Receptores Imunológicos/imunologia , Aloenxertos , Animais , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/transplante , Lectinas Tipo C/genética , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptores Imunológicos/genética
18.
Front Immunol ; 10: 2216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632390

RESUMO

Dendritic cell (DC)-based immunotherapies are being explored for over 20 years and found to be very safe. Most often, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4)-induced monocyte-derived DCs (moDCs) are being used, which have demonstrated some life-prolonging benefit to patients of multiple tumors. However, the limited clinical response and efficacy call for the development of more potent DCs. CD137L-DC may meet this demand. CD137L-DCs are a novel type of monocyte-derived inflammatory DCs that are induced by CD137 ligand (CD137L) agonists. CD137L is expressed on the surface of antigen-presenting cells, including monocytes, and signaling of CD137L into monocytes induces their differentiation to CD137L-DCs. CD137L-DCs preferentially induce type 1 T helper (Th1) cell polarization and strong type 1 CD8+ T cell (Tc1) responses against tumor-associated viral antigens. The in vitro T cell-stimulatory capacity of CD137L-DCs is superior to that of conventional moDCs. The transcriptomic profile of CD137L-DC is highly similar to that of in vivo DCs at sites of inflammation. The strict activation dependence of CD137 expression and its restricted expression on activated T cells, NK cells, and vascular endothelial cells at inflammatory sites make CD137 an ideally suited signal for the induction of monocyte-derived inflammatory DCs in vivo. These findings and their potency encouraged a phase I clinical trial of CD137L-DCs against Epstein-Barr virus-associated nasopharyngeal carcinoma. In this review, we introduce and summarize the history, the characteristics, and the transcriptional profile of CD137L-DC, and discuss the potential development and applications of CD137L-DC.


Assuntos
Ligante 4-1BB/imunologia , Diferenciação Celular/imunologia , Células Dendríticas , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4/imunologia , Imunização , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Ligante 4-1BB/genética , Ensaios Clínicos Fase I como Assunto , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/transplante , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Humanos , Monócitos/imunologia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Linfócitos T/imunologia , Linfócitos T/patologia
19.
Front Immunol ; 10: 2353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649669

RESUMO

Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies.


Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Células Dendríticas , Linfócitos do Interstício Tumoral , Melanoma , Linfócitos T Reguladores , Vacinação , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Seguimentos , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Metástase Neoplásica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
20.
JCI Insight ; 4(18)2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31487265

RESUMO

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.


Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Calcitriol/administração & dosagem , Células Dendríticas/imunologia , Epitopos Imunodominantes/administração & dosagem , Transferência Adotiva , Animais , Doença Antimembrana Basal Glomerular/diagnóstico , Doença Antimembrana Basal Glomerular/imunologia , Apresentação do Antígeno/efeitos dos fármacos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Células CHO , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Cricetulus , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/transplante , Modelos Animais de Doenças , Feminino , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Tolerância Imunológica/efeitos dos fármacos , Epitopos Imunodominantes/imunologia , Memória Imunológica/efeitos dos fármacos , Injeções Subcutâneas , Lipossomos , Linfonodos/citologia , Camundongos , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo
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