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1.
Cell Death Differ ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001780

RESUMO

The metabolism-controlled differentiation of αß T cells has been well documented; however, the role of a metabolism program in γδ T cell differentiation and function has not been clarified. Here, using CD2-cre; mTORC1 Raptor-f/f, and mTORC2 Rictor-f/f mice (KO mice), we found that mTORC1, but not mTORC2, was required for the proliferation and survival of peripheral γδ T cells, especially Vγ4 γδ T cells. Moreover, mTORC1 was essential for both γδ T1 and γδ Τ17 differentiation, whereas mTORC2 was required for γδ T17, but not for γδ Τ1, differentiation. We further studied the underlying molecular mechanisms and found that depletion of mTORC1 resulted in the increased expression of SOCS1, which in turn suppressed the key transcription factor Eomes, consequentially reducing IFN-γ production. Whereas the reduced glycolysis resulted in impaired γδ Τ17 differentiation in Raptor KO γδ T cells. In contrast, mTORC2 potentiated γδ Τ17 induction by suppressing mitochondrial ROS (mitoROS) production. Consistent with their cytokine production profiles, the Raptor KO γδ T cells lost their anti-tumor function both in vitro and in vivo, whereas both Raptor and Rictor KO mice were resistant to imiquimod (IMQ)-induced psoriasis-like skin pathogenesis. In summary, we identified previously unknown functions of mTORC1 and mTORC2 in γδ T cell differentiation and clarified their divergent roles in mediating the activity of γδ T cells in tumors and autoimmunity.

2.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911547

RESUMO

PURPOSE: This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. EXPERIMENTAL DESIGN: Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors. RESULTS: Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8+ T and CD4+ T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8+ T cells was independently predictive of poor overall survival and event-free survival. CONCLUSIONS: T-cell senescence and exhaustion, together with impaired NK and γδ T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.

3.
J Biol Chem ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819008

RESUMO

Serum amyloid A (SAA), one of the major highly conserved acute phase proteins in most mammals, is predominantly produced by hepatocytes and also by a variety of cells in extra-hepatic tissues. It is well known that the expression of SAA is sharply increased in bacterial infections. However, the exact physiological function of SAA during bacterial infection remains unclear. Herein, we showed that SAA expressed significantly increased in abscesses of Staphylococcus aureus (S. aureus) cutaneous infected mice, which exert direct antibacterial effects by binding to the bacterial cell surface and disrupting the cell membrane at acidic condition. Mechanically, SAA disrupts anionic liposomes by spontaneously forming small vesicles or micelles under acidic conditions. Especially, the N-terminal region of SAA is necessary for membrane disruption and bactericidal activity. Furthermore, we found that mice deficient of SAA1/2 was more susceptible to infection by S. aureus. In addition, the expression of SAA in infected skin was regulated by IL-6. Taken together, these findings support a key role of the SAA in host defense and may provide a novel therapeutic strategy for cutaneous bacterial infection.

4.
J Oncol ; 2019: 5935640, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772580

RESUMO

Inflammation and immunity are thought as risk factors for uterine leiomyoma; however, detailed reports on this topic are scarce. The present study aimed to analyze the characteristics of immune function and clinical significance of circulating CD4/CD8 T, NK, and γδ T cells in reproductive females with uterine leiomyoma. We analyzed the above-mentioned cells in 30 reproductive females with uterine leiomyoma and 68 healthy females using flow cytometry. After that, the correlation between function of immune cells and clinical phenotypes was analyzed. Compared with healthy controls, central memory (CM) CD4/CD8 T cells as well as Treg and Tfh cells were notably increased in leiomyoma patients; however, NK and γδ T cells were decreased in patients. Moreover, such alterations of these cells in patients with leiomyoma were associated with shorter menstrual cycles, longer menstrual period, anemia, pelvic lesions, more and larger myomas, and higher levels of CA125. Additionally, the increased Tfh1/Tfh2 ratio and Tfh17 were significantly associated with longer menstrual period, more myomas, and higher CA125 levels independent of age in patients with uterine leiomyoma. In conclusion, hallmarks of peripheral immune function are remarkably correlated with clinical phenotypes in reproductive females with uterine leiomyoma. This preliminary work may provide proof-of-concept for evaluating efficacy of treatment and prognosis of reproductive females with uterine leiomyoma with the help of quantitative analysis of peripheral immune function, which may inspire performing further investigations on the relevance of immune function with different diseases.

5.
Oncogenesis ; 8(11): 65, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685806

RESUMO

TFF3 has been identified as a novel biomarker to distinguish between lung adenocarcinoma (ADC) and lung squamous-cell carcinoma (SCC). Herein, we determined the oncogenic functions of TFF3 and demonstrated the potential of pharmacological inhibition of TFF3 in lung ADC using a novel small-molecule inhibitor of TFF3 dimerization (AMPC). Forced expression of TFF3 in lung ADC cells enhanced cell proliferation and survival, increased anchorage-independent growth, cancer stem cell behavior, growth in 3D Matrigel, and cell migration and invasion. In contrast, depleted expression of TFF3 suppressed these cellular functions. Mechanistically, TFF3 exerted its oncogenic function through upregulation of ARAF and hence enhanced downstream activation of MEK1/2 and ERK1/2. Pharmacological inhibition of TFF3 by AMPC, resulted in markedly decreased cell survival, proliferation, 3D growth and foci formation, and impaired tumor growth in a xenograft mouse model. Moreover, the combination of various MEK1/2 inhibitors with AMPC exhibited synergistic inhibitory effects on lung ADC cell growth. In conclusion, this study provides the first evidence that TFF3 is a potent promoter of lung ADC progression. Targeting TFF3 with a novel small-molecule inhibitor alone or in combination with conventional MEK1/2 inhibitors are potential strategies to improve the outcome of lung ADC.

6.
Nat Commun ; 10(1): 3859, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455769

RESUMO

Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.


Assuntos
Switching de Imunoglobulina/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Células Vero , Infecção por Zika virus/virologia
7.
Biomaterials ; 222: 119397, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442884

RESUMO

Immune cell therapy presents a paradigm for the treatment of malignant tumors. Human Vγ9Vδ2 T cells, a subset of peripheral γδ T cells, have been shown to have promising anti-tumor activity. However, new methodology on how to achieve a stronger anti-tumor activity of Vγ9Vδ2 T cells is under continuous investigation. In this work, we used selenium nanoparticles (SeNPs) to strengthen the anti-tumor cytotoxicity of Vγ9Vδ2 T cells. We found SeNPs pretreated γδ T cells had significantly stronger cancer killing and tumor growth inhibition efficacy when compared with γδ T cells alone. Simultaneously, SeNPs pretreatment could significantly upregulate the expression of cytotoxicity related molecules including NKG2D, CD16, and IFN-γ, meanwhile, downregulate PD-1 expression of γδ T cells. Importantly, we observed that SeNPs promoted tubulin acetylation modification in γδ T cells through interaction between microtubule network and lysosomes since the latter is the primary resident station of SeNPs shown by confocal visualization. In conclusion, SeNPs could significantly potentiate anti-tumor cytotoxicity of Vγ9Vδ2 T cells, and both cytotoxicity related molecules and tubulin acetylation were involved in fine-tuning γδ T cell toxicity against cancer cells. Our present work demonstrated a new strategy for further enhancing anti-tumor cytotoxicity of human Vγ9Vδ2 T cells by using SeNPs-based nanotechnology, not gene modification, implicating SeNPs-based nanotechnology had a promising clinical perspective in the γδ T cell immunotherapy for malignant tumors.

8.
J Immunother Cancer ; 7(1): 201, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366386

RESUMO

BACKGROUND: Interleukin(IL)-30/IL-27p28 production by Prostate Cancer (PC) Stem-Like Cells (SLCs) has proven, in murine models, to be critical to tumor onset and progression. In PC patients, IL-30 expression by leukocytes infiltrating PC and draining lymph nodes correlates with advanced disease grade and stage. Here, we set out to dissect the role of host immune cell-derived IL-30 in PC growth and patient outcome. METHODS: PC-SLCs were implanted in wild type (WT) and IL-30 conditional knockout (IL-30KO) mice. Histopathological and cytofluorimetric analyses of murine tumors and lymphoid tissues prompted analyses of patients' PC samples and follow-ups. RESULTS: Implantation of PC-SLCs in IL-30KO mice, gave rise to slow growing tumors characterized by apoptotic events associated with CD4+T lymphocyte infiltrates and lack of CD4+Foxp3+ T regulatory cells (Tregs). IL-30 knockdown in PC-SLCs reduced cancer cell proliferation, vascularization and intra-tumoral Indoleamine 2,3-Dioxygenase (IDO)+CD11b+Gr-1+ myeloid-derived cells (MDCs) and led to a significant delay in tumor growth and increase in survival. IL-30-silenced tumors developed in IL-30KO mice, IL-30-/-tumors, lacked vascular supply and displayed frequent apoptotic cancer cells entrapped by perforin+TRAIL+CD3+Tlymphocytes, most of which had a CD4+T phenotype, whereas IL-10+TGFß+Foxp3+Tregs were lacking. IL-30 silencing in PC-SLCs prevented lung metastasis in 73% of tumor-bearing WT mice and up to 80% in tumor-bearing IL-30KO mice. In patients with high-grade and locally advanced PC, those with IL-30-/-tumors, showed distinct intra-tumoral cytotoxic granule-associated RNA binding protein (TIA-1)+CD4+Tlymphocyte infiltrate, rare Foxp3+Tregs and a lower biochemical recurrence rate compared to patients with IL-30+/+tumors in which IL-30 is expressed in both tumor cells and infiltrating leukocytes. CONCLUSION: The lack of host leukocyte-derived IL-30 inhibits Tregs expansion, promotes intra-tumoral infiltration of CD4+T lymphocytes and cancer cell apoptosis. Concomitant lack of MDC influx, obtained by IL-30 silencing in PC-SLCs, boosts cytotoxic T lymphocyte activation and cancer cell apoptosis resulting in a synergistic tumor suppression with the prospective benefit of better survival for patients with advanced disease.

9.
Cell Mol Immunol ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171862

RESUMO

γδ T cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types. Potential applications include the adoptive transfer of in vitro-expanded γδ T cells. Therefore, it is important to optimize the culture conditions to enable maximal proliferative and functional activity. Vitamin C (L-ascorbic acid) is an essential vitamin with multiple effects on immune cells. It is a cofactor for several enzymes, has antioxidant activity, and is an epigenetic modifier. Here, we investigated the effects of vitamin C (VC) and its more stable derivative, L-ascorbic acid 2-phosphate (pVC), on the proliferation and effector function of human γδ T cells stimulated with zoledronate (ZOL) or synthetic phosphoantigens (pAgs). VC and pVC did not increase γδ T-cell expansion within ZOL- or pAg-stimulated PBMCs, but increased the proliferation of purified γδ T cells and 14-day-expanded γδ T-cell lines in response to γδ T-cell-specific pAgs. VC reduced the apoptosis of γδ T cells during primary stimulation. While pVC did not prevent activation-induced death of pAg-restimulated γδ T cells, it enhanced the cell cycle progression and cellular expansion. Furthermore, VC and pVC enhanced cytokine production during primary activation, as well as upon pAg restimulation of 14-day-expanded γδ T cells. VC and pVC also increased the oxidative respiration and glycolysis of γδ T cells, but stimulus-dependent differences were observed. The modulatory activity of VC and pVC might help to increase the efficacy of γδ T-cell expansion for adoptive immunotherapy.

10.
J Nanobiotechnology ; 17(1): 67, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101112

RESUMO

BACKGROUND: Immunochromatographic strips (ICSs) are a practical tool commonly used in point-of-care testing (POCT) applications. However, ICSs that are currently available have low sensitivity and require expensive equipment for quantitative analysis. These limitations prohibit their extensive use in areas where medical resources are scarce. METHODS: We developed a novel POCT platform by integrating a gas generation biosensor with Au@Pt Core/Shell nanoparticle (Au@PtNPs)-based ICSs (G-ICSs). The resulting G-ICSs enabled the convenient and quantitative assessment of a target protein using the naked eye, without the need for auxiliary equipment or complicated computation. To assess this platform, C-reactive protein (CRP), a biomarker commonly used for the diagnosis of acute, infectious diseases was chosen as a proof-of-concept test. RESULTS: The linear detection range (LDR) of the G-ICSs for CRP was 0.05-6.25 µg/L with a limit of detection (LOD) of 0.041 µg/L. The G-ICSs had higher sensitivity and wider LDR when compared with commonly used AuNPs and fluorescent-based ICSs. When compared with results from a chemiluminescent immunoassay, G-ICS concordance rates for CRP detection in serum samples ranged from 93.72 to 110.99%. CONCLUSIONS: These results demonstrated that G-ICSs have wide applicability in family diagnosis and community medical institutions, especially in areas with poor medical resources.


Assuntos
Biomarcadores/análise , Proteína C-Reativa/análise , Gases/análise , Ouro/química , Nanopartículas Metálicas/química , Anticorpos Monoclonais/química , Técnicas Biossensoriais/métodos , Cromatografia de Afinidade/métodos , Peróxido de Hidrogênio/química , Limite de Detecção , Oxirredução , Oxigênio/química , Tamanho da Partícula , Testes Imediatos , Impressão Tridimensional , Propriedades de Superfície
12.
J Colloid Interface Sci ; 549: 50-62, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31015056

RESUMO

Spinal cord injury (SCI) can cause locomotor dysfunctions and sensory deficits. Evidence shows that functional nanodrugs can regulate macrophage polarization and promote anti-inflammatory cytokine expression, which is feasible in SCI immunotherapeutic treatments. Molybdenum disulfide (MoS2) nanomaterials have garnered great attention as potential carriers for therapeutic payload. Herein, we synthesize MoS2@PEG (MoS2 = molybdenum disulfide, PEG = poly (ethylene glycol)) nanoflowers as an effective carrier for loading etanercept (ET) to treat SCI. We characterize drug loading and release properties of MoS2@PEG in vitro and demonstrate that ET-loading MoS2@PEG obviously inhibits the expression of M1-related pro-inflammatory markers (TNF-α, CD86 and iNOS), while promoting M2-related anti-inflammatory markers (Agr1, CD206 and IL-10) levels. In vivo, the mouse model of SCI shows that long-circulating ET-MoS2@PEG nanodrugs can effectively extravasate into the injured spinal cord up to 96 h after SCI, and promote macrophages towards M2 type polarization. As a result, the ET-loading MoS2@PEG administration in mice can protect survival motor neurons, thus, reducing injured areas at central lesion sites, and significantly improving locomotor recovery. This study demonstrates the anti-inflammatory and neuroprotective activities of ET-MoS2@PEG and promising utility of MoS2 nanomaterial-mediated drug delivery.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dissulfetos/química , Etanercepte/farmacologia , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Molibdênio/química , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Portadores de Fármacos , Liberação Controlada de Fármacos , Etanercepte/uso terapêutico , Feminino , Humanos , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho da Partícula , Permeabilidade , Polietilenoglicóis , Células RAW 264.7 , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Propriedades de Superfície
13.
Front Immunol ; 10: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814995

RESUMO

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Fator 1 de Transcrição de Linfócitos T/metabolismo , Viroses/etiologia , Viroses/metabolismo , Transferência Adotiva , Animais , Sobrevivência Celular , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/terapia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Transgênicos , Fator 1 de Transcrição de Linfócitos T/genética , Quimeras de Transplante , Carga Viral , Viroses/terapia
14.
Pathog Dis ; 77(1)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753412

RESUMO

Macrophages are the primary host target cells of Mycobacterium tuberculosis (M. tb). As a subunit of immunoregulatory cytokines IL-27 and IL-35, Epstein-Barr virus-induced gene 3 (EBI3) has typically been explored as the secreted form and assessed in terms of its effects triggered by extracellular EBI3. However, little is known about intracellular EBI3 function. In the current study, we report that EBI3 production by macrophages is elevated in TB patients. We further demonstrate that increased EBI3 accumulates in virulent M. tb-treated murine macrophages. Eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) binds to intracellular EBI3 to reduce Lys48 (K48)-linked ubiquitination of EBI3, leading to EBI3 accumulation. Moreover, the intracellular EBI3 inhibits caspase-3-mediated apoptosis in M. tb-treated macrophages. Herein, we propose a novel mechanism for accumulating intracellular EBI3 and its regulation of macrophage apoptosis in response to virulent M. tb.


Assuntos
Apoptose/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Mycobacterium tuberculosis/imunologia , Receptores de Citocinas/metabolismo , Tuberculose/imunologia , Tuberculose/metabolismo , Animais , Estudos de Casos e Controles , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Contagem de Leucócitos , Camundongos , Camundongos Knockout , Fator 1 de Elongação de Peptídeos/metabolismo , Ligação Proteica , RNA Interferente Pequeno/genética , Tuberculose/microbiologia
15.
J Immunother Cancer ; 7(1): 36, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736852

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA. CASE PRESENTATION: A 30-year-old male ( https://www.clinicaltrials.gov/ ID: NCT02425735) was diagnosed with recurrent mediastinal lymph node metastasis after liver transplantation because of Cholangiocarcinoma (stage IV). In the course of his therapy sessions, he only received allogenic γδ T cell immunotherapy from August, 2017 through February, 2018 (8 infusions in total). γδ T cells were expanded from peripheral blood mononuclear cells (PBMCs) of healthy donor, and ~ 4 × 108 cells were adoptive transferred to the patient. CONCLUSION: In the above case report of the Cholangiocarcinoma (stage IV) patient who had received liver transplantation and afterward was diagnosed with recurrent mediastinal lymph node metastasis, we clinically proved that allogenic γδ T cell treatment had no adverse effects. We observed that allogenic γδ T cell treatments positively regulated peripheral immune functions of the patient, depleted tumor activity, improved quality of life, and prolonged his life span. After 8 γδ T cell treatments, the size of lymph nodes was remarkably reduced with activity depletion. This clinical work suggested that allogenic γδ T cell immunotherapy could be developed into a promising therapy drug for CCA.

16.
J Cell Physiol ; 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786006

RESUMO

Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.

17.
Proc Natl Acad Sci U S A ; 115(52): E12313-E12322, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30541887

RESUMO

Dendritic cells (DCs) play pivotal roles in maintaining intestinal homeostasis, but how the DCs regulate diverse immune networks on homeostasis breakdown remains largely unknown. Here, we report that, in response to epithelial barrier disruption, colonic DCs regulate the differentiation of type 1 regulatory T (Tr1) cells through p38α-dependent IL-27 production to initiate an effective immune response. Deletion of p38α in DCs, but not in T cells, led to increased Tr1 and protected mice from dextran sodium sulfate-induced acute colitis and chronic colitis-associated colorectal cancer. We show that higher levels of IL-27 in p38α-deficient colonic cDC1s, but not cDC2s, were responsible for the increase of Tr1 cells. Moreover, p38α-dependent IL-27 enhanced IL-22 secretion from intestinal group 3 innate lymphoid cells and protected epithelial barrier function. In p38α-deficient DCs, the TAK1-MKK4/7-JNK-c-Jun axis was hyperactivated, leading to high IL-27 levels, and inhibition of the JNK-c-Jun axis suppressed IL-27 expression. ChIP assay revealed direct binding of c-Jun to the promoter of Il27p28, which was further enhanced in p38α-deficient DCs. In summary, here we identify a key role for p38α signaling in DCs in regulating intestinal inflammatory response and tumorigenesis, and our finding may provide targets for the treatment of inflammatory intestinal diseases.


Assuntos
Colite/enzimologia , Colo/imunologia , Neoplasias Colorretais/enzimologia , Células Dendríticas/enzimologia , Proteína Quinase 14 Ativada por Mitógeno/imunologia , Animais , Carcinogênese , Colite/genética , Colite/imunologia , Colite/patologia , Colo/enzimologia , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Células Dendríticas/imunologia , Feminino , Humanos , Interleucina-27/genética , Interleucina-27/imunologia , Intestinos/imunologia , Intestinos/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/genética , Linfócitos T Reguladores/imunologia
18.
Proc Natl Acad Sci U S A ; 115(44): E10505-E10514, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30309962

RESUMO

Human BCL-2-associated death promoter (hBAD) is an apoptosis-regulatory protein mediating survival signals to carcinoma cells upon phosphorylation of Ser99, among other residues. Herein, we screened multiple small-molecule databases queried in a Laplacian-modified naive Bayesian-based cheminformatics platform and identified a Petasis reaction product as a site-specific inhibitor for hBAD phosphorylation. Based on apoptotic efficacy against mammary carcinoma cells, N-cyclopentyl-3-((4-(2,3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) benzamide (NPB) was identified as a potential lead compound. In vitro biochemical analyses demonstrated that NPB inhibited the phosphorylation of hBAD specifically on Ser99. NPB was observed to exert this effect independently of AKT and other kinase activities despite the demonstration of AKT-mediated BAD-Ser99 phosphorylation. Using a structure-based bioinformatics platform, we observed that NPB exhibited predicted interactions with hBAD in silico and verified the same by direct binding kinetics. NPB reduced phosphorylation of BAD-Ser99 and enhanced caspase 3/7 activity with associated loss of cell viability in various human cancer cell lines derived from mammary, endometrial, ovarian, hepatocellular, colon, prostatic, and pancreatic carcinoma. Furthermore, by use of a xenograft model, it was observed that NPB, as a single agent, markedly diminished BAD phosphorylation in tumor tissue and significantly inhibited tumor growth. Similar doses of NPB utilized in acute toxicity studies in mice did not exhibit significant effects. Hence, we report a site-specific inhibitor of BAD phosphorylation with efficacy in tumor models.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Piperazinas/farmacologia , Serina/química , Proteína de Morte Celular Associada a bcl/antagonistas & inibidores , Antineoplásicos/química , Apoptose , Benzamidas/química , Proliferação de Células , Bases de Dados Factuais , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos , Células MCF-7 , Fosforilação , Piperazinas/química , Interferência de RNA , Bibliotecas de Moléculas Pequenas , Ressonância de Plasmônio de Superfície
19.
Cell Physiol Biochem ; 48(5): 1882-1893, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30092590

RESUMO

BACKGROUND/AIMS: We evaluated the clinical effectiveness of irreversible electroporation (IRE) in combination with immunotherapy using allogenic natural killer cells (NK) for stage IV hepatocellular carcinoma (HCC). METHODS: The study involved 40 patients with stage IV HCC who were divided equally into two groups: 1) simple IRE; and 2) IRE plus allogenic NK cells (IRE-NK); we mainly assessed the overall survival (OS). RESULTS: The effect of the IRE-NK treatment was synergistic, i.e., not only did it enhance immune function, it also decreased alpha-fetoprotein expression and showed significantly good clinical effectiveness. At the median 7.6-month follow-up (range, 3.8-12.1 months), median OS was higher in the IRE-NK group (10.1 months) than in the IRE group (8.9 months, P = 0.0078). CONCLUSION: IRE combined with allogeneic NK cell immunotherapy significantly increases the median OS of patients with stage IV HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Células Matadoras Naturais/transplante , Neoplasias Hepáticas/terapia , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica , Eletroporação , Feminino , Humanos , Imunoterapia/efeitos adversos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Fígado/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Imagem por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , alfa-Fetoproteínas/metabolismo
20.
Front Immunol ; 9: 1127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875775

RESUMO

Follicular helper CD4+ T (TFH) cells are critical for optimal B-cell-mediated humoral immunity by initiating, fueling, and sustaining germinal center reactions. The differentiation of TFH cells relies on multiple intrinsic and extrinsic factors; however, the details by which these factors are integrated to coordinate TFH differentiation are largely unknown. In this study, using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) viral infection, we demonstrate that mTOR complex 2 (mTORC2) kinase integrates TCR signaling and ICOS-mediated co-stimulation to promote late differentiation and functional maturation of virus-specific TFH cells. Specifically, mTORC2 functions to maintain TFH lineage specifications, including phenotypes, migratory characteristics, and functional properties. Thus, our results highlight the importance of mTORC2 in guarding TFH phenotypic and functional maturation.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Viroses/imunologia , Viroses/metabolismo , Animais , Biomarcadores , Complexo CD3/metabolismo , Linhagem da Célula , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Imunidade Humoral , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Viroses/virologia
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