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1.
Nat Commun ; 12(1): 5857, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615877

RESUMO

The recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.


Assuntos
Imunidade , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Humanos , Imunoterapia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/terapia , Neuropeptídeos/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Transdução de Sinais
2.
Nat Commun ; 12(1): 5764, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599187

RESUMO

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Homeostase , Isoantígenos/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas Ligadas por GPI/deficiência , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Camundongos Knockout , Prognóstico , Receptores de Superfície Celular/deficiência , Análise de Célula Única , Transcrição Genética
3.
Cell Rep ; 36(8): 109596, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433060

RESUMO

Germline alterations of the NF2 gene cause neurofibromatosis type 2, a syndrome manifested with benign tumors, and Nf2 deletion in mice also results in slow tumorigenesis. As a regulator of the Hippo signaling pathway, NF2 induces LATS1/2 kinases and consequently represses YAP/TAZ. YAP/TAZ oncoproteins are also inhibited by motin family proteins (Motins). Here, we show that the Hippo signaling is fine-tuned by Motins in a NF2-dependent manner, in which NF2 recruits E3 ligase RNF146 to facilitate ubiquitination and subsequent degradation of Motins. In the absence of NF2, Motins robustly accumulate to restrict full activation of YAP/TAZ and prevent rapid tumorigenesis. Hence, NF2 deficiency not only activates YAP/TAZ by inhibiting LATS1/2 but also stabilizes Motins to keep YAP/TAZ activity in check. The upregulation of Motins upon NF2 deletion serves as a strategy for avoiding uncontrolled perturbation of the Hippo signaling and may contribute to the benign nature of most NF2-mutated tumors.

5.
Redox Biol ; 46: 102079, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34454163

RESUMO

Liver injuries induced by various stimuli share in common an acute inflammatory response, in which circulating macrophages home to the liver parenchyma to participate in the regulation of repair, regeneration, and fibrosis. In the present study we investigated the role of hepatocyte-derived C-C motif ligand 7 (CCL7) in macrophage migration during liver injury focusing on its transcriptional regulation. We report that CCL7 expression was up-regulated in the liver by lipopolysaccharide (LPS) injection (acute liver injury) or methionine-and-choline-deficient (MCD) diet feeding (chronic liver injury) paralleling increased macrophage infiltration. CCL7 expression was also inducible in hepatocytes, but not in hepatic stellate cells or in Kupffer cells, by LPS treatment or exposure to palmitate in vitro. Hepatocyte-specific deletion of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, resulted in a concomitant loss of CCL7 induction and macrophage infiltration in the murine livers. Of interest, BRG1-induced CCL7 transcription and macrophage migration was completely blocked by the antioxidant N-acetylcystine. Further analyses revealed that BRG1 interacted with activator protein 1 (AP-1) to regulate CCL7 transcription in hepatocytes in a redox-sensitive manner mediated in part by casein kinase 2 (CK2)-catalyzed phosphorylation of BRG1. Importantly, a positive correlation between BRG1/CCL7 expression and macrophage infiltration was identified in human liver biopsy specimens. In conclusion, our data unveil a novel role for BRG1 as a redox-sensitive activator of CCL7 transcription.


Assuntos
DNA Helicases , Proteínas Nucleares , Animais , Células Cultivadas , Quimiocina CCL7/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxirredução , Fatores de Transcrição
6.
Front Cell Dev Biol ; 9: 617549, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249900

RESUMO

Malignant colorectal cancers (CRCs) are characterized by enhanced migration and invasion thus acquiring the ability to metastasize. We have previously shown that the small GTPase TC10-like (TCL) contributes to aggressive migration and invasion in malignant CRC cells. TCL expression is differentially expressed in CRC cells and can be upregulated by hypoxia although the underlying epigenetic mechanism is not fully appreciated. Here, we report that differential TCL expression in CRC cells appeared to be associated with histone H3K9 methylation. RNAi screening revealed that the lysine demethylase KDM4B was essential for TCL transcription in CRC cells. KDM4B interacted with and was recruited by the sequence-specific transcription factor ETS-related gene 1 (ERG1) to the TCL promoter to activate transcription. Mechanistically, KDM4B mediated H3K9 demethylase facilitated the assembly of pre-initiation complex (PIC) on the TCL promoter. KDM4B knockdown attenuated migration and invasion of CRC cells. Importantly, KDM4B expression was upregulated in human CRC specimens of advanced stages compared to those of lower grades and associated with poor prognosis. Together, these data uncover a novel epigenetic mechanism underlying malignant transformation of CRC cells and suggest that KDM4B may be considered as a therapeutic target in CRC intervention.

7.
Front Cell Dev Biol ; 9: 664375, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249916

RESUMO

The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-ß activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-ß-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-ß signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-ß-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-ß regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.

8.
Sci Total Environ ; 796: 148964, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34273841

RESUMO

Medical waste (MW) has exploded since the COVID-19 pandemic and aroused great concern to MW disposal. Meanwhile, the energy recovery for MW disposal is necessary due to high heat value of MW. Harmless disposal of MW with economically and environmentally sustainable technologies along with higher energy recovery is urgently required, and their energy recovery efficiencies and environmental impacts reduction due to energy recovery are key issues. In this study, five MW disposal technologies, i.e. rotary kiln incineration, pyrolysis incineration, plasma melting, steam sterilization and microwave sterilization, were evaluated and compared via energy recovery analysis (ERA), life cycle assessment (LCA), and life cycle costing (LCC) methods. Furthermore, three MW incineration technologies with further energy recovery and two sterilization followed by co-incineration technologies were analyzed to explore their improvement potential of energy recovery and environment benefits via scenario analysis. ERA results reveal that the energy recovery efficiencies of "steam and microwave sterilization + incineration" are the highest (≥83.4%), while that of the plasma melting is the lowest (19.2%). LCA results show that "microwave sterilization + landfill" outperforms others while the plasma melting exhibits the worst, electricity is the most significant contributor to the environmental impacts of five technologies. Scenario analysis shows that the overall environmental impact of all technologies reduced by at least 45% after further heat utilization. LCC results demonstrate that pyrolysis incineration delivers the lowest economic cost, while plasma melting is the highest. Co-incineration of sterilized MW and municipal solid waste could be recommended.


Assuntos
COVID-19 , Eliminação de Resíduos de Serviços de Saúde , Eliminação de Resíduos , China , Humanos , Pandemias , SARS-CoV-2
9.
Sci Transl Med ; 13(604)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321321

RESUMO

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.


Assuntos
Neoplasias , Preparações Farmacêuticas , Animais , Células Endoteliais , Humanos , Imunoterapia , Camundongos , Neoplasias/tratamento farmacológico , Microambiente Tumoral
10.
Front Cell Dev Biol ; 9: 617073, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816466

RESUMO

Multiple organ failure is one of the most severe consequences in patients with septic shock. Liver injury is frequently observed during this pathophysiological process. In the present study we investigated the contribution of Brahma related gene 1 (BRG1), a chromatin remodeling protein, to septic shock induced liver injury. When wild type (WT) and liver conditional BRG1 knockout (LKO) mice were injected with lipopolysaccharide (LPS), liver injury was appreciably attenuated in the LKO mice compared to the WT mice as evidenced by plasma ALT/AST levels, hepatic inflammation and apoptosis. Of interest, there was a down-regulation of sterol response element binding protein 1a (SREBP1a), known to promote liver injury, in the LKO livers compared to the WT livers. BRG1 did not directly bind to the SREBP1a promoter. Instead, BRG1 was recruited to the toll-like receptor 4 (TLR4) promoter and activated TLR4 transcription. Ectopic TLR4 restored SREBP1a expression in BRG1-null hepatocytes. Congruently, adenovirus carrying TLR4 or SREBP1a expression vector normalized liver injury in BRG1 LKO mice injected with LPS. Finally, a positive correlation between BRG1 and TLR4 expression was detected in human liver biopsy specimens. In conclusion, our data demonstrate that a BRG1-TLR4-SREBP1a axis that mediates LPS-induced liver injury in mice.

11.
Waste Manag ; 126: 388-399, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33827006

RESUMO

The COVID-19 pandemic attracts concerns globally and leads to an exponential increase in medical waste generation, and disposal of medical waste is an urgent need for preventing the epidemic spread. Emergency disposal scenarios of medical waste generated during the COVID-19 pandemic require a systematic assessment to quantify their potential environmental impacts. The environmental impacts and key factors of three movable disposal scenarios (i.e. incineration disposal vehicle, movable steam and microwave sterilization equipment both followed by co-incineration with municipal solid waste) were quantified via life cycle assessment approach. Furthermore, the environmental impacts of three movable disposal and two co-incineration scenarios were compared via life cycle assessment by expanding system boundaries. The results show that co-incineration with municipal solid waste has the lowest environmental impacts due to environmental benefits produced by power generation, while co-incineration with hazardous waste is the highest due to the high energy consumption. Energy consumption (i.e. kerosene, electricity and diesel) are the key factors for three movable disposal scenarios. For movable steam and microwave sterilization equipment followed by co-incineration with municipal solid waste, power generation from incinerating disinfected medical waste has significant beneficial environmental impacts due to avoided impacts of electricity consumption. The recommendations for improvement of the emergency disposal and management of medical waste during the COVID-19 pandemic globally and other serious epidemic in the future are provided.


Assuntos
COVID-19 , Resíduos de Serviços de Saúde , Eliminação de Resíduos , Gerenciamento de Resíduos , Animais , China , Humanos , Incineração , Estágios do Ciclo de Vida , Pandemias , SARS-CoV-2 , Resíduos Sólidos/análise , Instalações de Eliminação de Resíduos
13.
Front Cell Dev Biol ; 9: 622866, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33718362

RESUMO

Sterol response element binding protein (SREBP) is a master regulator of cellular lipogenesis. One key step in the regulation of SREBP activity is its sequential cleavage and trans-location by several different proteinases including SREBP cleavage activating protein (SCAP). We have previously reported that Brahma related gene 1 (BRG1) directly interacts with SREBP1c and SREBP2 to activate pro-lipogenic transcription in hepatocytes. We report here that BRG1 deficiency resulted in reduced processing and nuclear accumulation of SREBP in the murine livers in two different models of non-alcoholic steatohepatitis (NASH). Exposure of hepatocytes to lipopolysaccharide (LPS) and palmitate (PA) promoted SREBP accumulation in the nucleus whereas BRG1 knockdown or inhibition blocked SREBP maturation. Further analysis revealed that BRG1 played an essential role in the regulation of SCAP expression. Mechanistically, BRG1 interacted with Sp1 and directly bound to the SCAP promoter to activate SCAP transcription. Forced expression of exogenous SCAP partially rescued the deficiency in the expression of SREBP target genes in BRG1-null hepatocytes. In conclusion, our data uncover a novel mechanism by which BRG1 contributes to SREBP-dependent lipid metabolism.

14.
Nat Immunol ; 22(3): 370-380, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33574619

RESUMO

During chronic infection and cancer, a self-renewing CD8+ T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8+ T cells diverge from other CD8+ subsets early after chronic viral infection. However, pathways guarding stem-like CD8+ T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8+ T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8+ lineage and prevents an alternative terminally exhausted cell fate.


Assuntos
Infecções por Arenaviridae/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Epigênese Genética , Células Precursoras de Linfócitos T/metabolismo , Transcrição Genética , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Linhagem da Célula , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/virologia , Transdução de Sinais
15.
Am J Physiol Cell Physiol ; 320(1): C142-C151, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33175574

RESUMO

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.


Assuntos
Adenocarcinoma/secundário , Queimaduras por Corrente Elétrica/patologia , Neoplasias do Colo/patologia , Neoplasias Hepáticas/secundário , Fígado/patologia , Microambiente Tumoral , Adenocarcinoma/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Queimaduras por Corrente Elétrica/genética , Queimaduras por Corrente Elétrica/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Front Cell Dev Biol ; 8: 340, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32478075

RESUMO

Liver fibrosis is a complex pathophysiological process to which many different cell types contribute. Endothelial cells play versatile roles in the regulation of liver fibrosis. The underlying epigenetic mechanism is not fully appreciated. In the present study, we investigated the role of BRG1, a chromatin remodeling protein, in the modulation of endothelial cells in response to pro-fibrogenic stimuli in vitro and liver fibrosis in mice. We report that depletion of BRG1 by siRNA abrogated TGF-ß or hypoxia induced down-regulation of endothelial marker genes and up-regulation of mesenchymal marker genes in cultured endothelial cells. Importantly, endothelial-specific BRG1 deletion attenuated CCl4 induced liver fibrosis in mice. BRG1 knockdown in vitro or BRG1 knockout in vivo was accompanied by the down-regulation of TWIST, a key regulator of endothelial phenotype. Mechanistically, BRG1 interacted with and was recruited to the TWIST promoter by HIF-1α to activate TWIST transcription. BRG1 silencing rendered a more repressive chromatin structure surrounding the TWIST promoter likely contributing to TWIST down-regulation. Inhibition of HIF-1α activity dampened liver fibrosis in mice. Similarly, pharmaceutical inhibition of TWIST alleviated liver fibrosis in mice. In conclusion, our data suggest that epigenetic activation of TWIST by BRG1 contributes to the modulation of endothelial phenotype and liver fibrosis. Therefore, targeting the HIF1α-BRG1-TWIST axis may yield novel therapeutic solutions to treat liver fibrosis.

17.
Nano Lett ; 20(6): 4084-4094, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32379462

RESUMO

Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.


Assuntos
Imunoterapia , Nanopartículas , Neoplasias , Antígenos de Neoplasias , Biomimética , Células Dendríticas , Humanos , Neoplasias/terapia
18.
Mol Carcinog ; 59(7): 775-782, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32166821

RESUMO

Immunotherapy has revolutionized cancer treatment for several hematologic and solid organ malignancies; however, pancreatic cancer remains unresponsive to conventional immunotherapies. Several characteristics of pancreatic cancer present challenges to successful treatment with immunotherapy, including its aggressive biology, poor immunogenicity, and abundant desmoplastic stroma which can impede effector T cell infiltration and promote an immunosuppressive microenvironment. In this review, we evaluate the current understanding of the immune and stromal landscapes of pancreatic cancer, discuss the successes and failures of stroma-targeted therapies, and highlight how stroma-directed therapies may be synergistic with immunotherapy.


Assuntos
Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/imunologia , Animais , Humanos , Imunoterapia/métodos
19.
Cancer Lett ; 470: 197-203, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783085

RESUMO

Mitochondria are known as essential biosynthetic, bioenergetic and signaling organelles, and play a critical role in cell differentiation, proliferation, and death. Nowadays, cancer is emergingly considered as a mitochondrial metabolic disease. Mitochondria also play an essential role in liver carcinogenesis. Liver cells are highly regenerative and require high energy. For that reason, a large number of mitochondria are present and functional in liver cells. Abnormalities in mitochondrial metabolism in human liver are known to be one of the carcinogenic factors. Interestingly, immune checkpoints regulate mitochondrial metabolic energetics of the tumor, the tumor microenvironment, as well as the tumor-specific immune response. This regulation forms a positive loop between the metabolic reprogramming of both cancer cells and immune cells. In this review, we discuss the evidence and mechanisms that mitochondria interplay with immune checkpoints to influence different steps of oncogenesis, as well as the potential of mitochondria as therapeutic targets for liver cancer therapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinogênese/patologia , Metabolismo Energético/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Mitocôndrias/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético/imunologia , Humanos , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
20.
Oncoimmunology ; 8(2): e1538440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713797

RESUMO

The CD28H/B7-H5 pathway is a newly identified pathway of the B7 family. In human peripheral blood, the receptor CD28H is preferentially expressed on naïve T cells and repetitive stimulation of T cells leads to the loss of CD28H expression. Here we examined the expression of the CD28H/B7-H5 pathway in human peripheral tissues, as well as in human cancers. We found that CD28H is preferentially expressed on T cells with tissue-resident phenotypes (TRM). Supporting that, stimulation via IL-15 and TGF-ß, presumably major cytokines essential for TRM cell homeostasis, sustains CD28H expression on T cells. The ligand B7-H5 is constitutively expressed on normal epithelium of human oral-gastrointestinal tracts. In human cancers, CD28H is preferentially present on tumor infiltrating lymphocytes (TILs) with TRM features and identifies a TRM subset with less cytotoxicity. Taken together, our studies suggest that the CD28H/B7-H5 pathway involves the interactions between TRM cells and epithelium, and could be important for human TRM homeostasis and function.

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