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1.
Cancer Discov ; 10(3): 345-347, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32127405

RESUMO

Although CD4+ FOXP3+ T regulatory (Treg) cells are well-known mediators of immunologic tolerance, their influences in the tumor microenviroment are incompletely understood. Writing in this issue of Cancer Discovery, Zhang and colleagues demonstrate that in pancreatic cancer, Treg cells promote the differentiation of tumor-restraining myofibroblastic cancer-associated fibroblasts, challenging the existing notion that Treg cells enable tumor progression.See related article by Zhang et al., p. 422.

2.
Nat Immunol ; 21(4): 442-454, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152508

RESUMO

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Macrófagos/imunologia , Tolerância a Antígenos Próprios/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Interferon gama/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
3.
Clin Anat ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065677

RESUMO

INTRODUCTION: Dissemination of research depends on published work being accessible. In many disciplines open access (OA) research is more frequently cited, although this has never before been demonstrated amongst anatomy publications. The objective of this study was to assess a selection of published anatomy papers to determine the effect of gold and bronze OA availability on citation rates. MATERIALS AND METHODS: Taken together, 625 peer-reviewed publications were identified from 2927 abstracts presented at meetings of AACA (2003-2010) and BACA (2000-2015). RESULTS: In total 18.75% (69 of 368) of papers presented at BACA and 21.79% (56 of 257) of those presented at AACA reached OA publication. Citation rates are significantly higher amongst OA papers as compared to non-OA papers presented at these two anatomy conferences (OA 18.95, Non-OA 15.14 p = 0.047). OA papers were most commonly themed around education and pure anatomy. CONCLUSIONS: The average OA publication rate of 20.0% in anatomical research arising from these conferences is significantly lower than the average rate for scientific research. Citation rates are significantly higher amongst OA anatomy papers presented at these two conferences.

4.
Oncogene ; 39(15): 3102-3113, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32055023

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to checkpoint blockade, such as anti-CTLA-4 and anti-PD-1. Galectin-9, a ß-galactoside-binding lectin, promotes immune suppression through T-cell inhibition, and programming of tolerogenic macrophages. Of all cancers tested, PDAC showed the highest expression of LGALS9 (galectin-9) mRNA. We analyzed formalin-fixed and paraffin-embedded specimens from 83 patients with PDAC stained for galectin-9. Using flow cytometry, we determined galectin-9 expression on immune cells from tumor and matched blood samples from 12 patients with resectable PDAC. Furthermore, we analyzed galectin-9 serum levels by enzyme-linked immunosorbent assay using serum samples from 70 patients with PDAC, from 36 individuals with benign pancreatic disease, and from 28 healthy controls. Galectin-9 was highly expressed in human PDAC compared with normal pancreas and present on both tumor and immune cells. Tumor-infiltrating immune cells, especially CD3+ T cells, showed upregulation of galectin-9 compared with immune cells from matched blood. Blood γδ T cells from PDAC patients had higher galectin-9 expression than γδ T cells from healthy individuals. Galectin-9 polarized macrophages toward a protumoral M2 phenotype leading to suppressed T-cell cytokine secretion. Furthermore, serum concentration of galectin-9 was able to discriminate PDAC from benign pancreatic disease and healthy individuals, and was prognostic for stage IV patients. Galectin-9 is a new biomarker for the detection of PDAC.

5.
Hepatology ; 71(2): 477-494, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31529720

RESUMO

BACKGROUND AND AIMS: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). APPROACH AND RESULTS: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution. CONCLUSIONS: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4+ T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.

6.
Cancer Discov ; 10(2): 270-287, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31744829

RESUMO

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a Kras G12D/Trp53 -/- LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. Asf1a deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161.

7.
Cancer Cell ; 37(1): 37-54.e9, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31883968

RESUMO

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.

8.
J Exp Med ; 217(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31727783

RESUMO

The role of IL-17 in cancer remains controversial. Emerging evidence suggests that during early oncogenesis IL-17 supports tumor growth, whereas in established tumors IL-17 production by γδ and Th17 cells potentiates antitumor immunity. Consequently, γδ and Th17 cells are attractive targets for immunotherapy in the IL-17 immune axis. To optimize IL-17-based immunotherapy, a deeper understanding of the cytokines dictating IL-17 production and the polarity of γδ and Th17 cells is critical. Here, we delve into the dichotomous roles of IL-17 in cancer and provide insight into the tumor microenvironment conducive for successful IL-17-based γδ and Th17 cell immunotherapy.

9.
Trends Cancer ; 5(11): 670-676, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31735286

RESUMO

Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.

10.
Nature ; 574(7777): 264-267, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578522

RESUMO

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA)1. However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.


Assuntos
Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Carcinogênese , Carcinoma Ductal Pancreático/microbiologia , Carcinoma Ductal Pancreático/patologia , Microbioma Gastrointestinal/imunologia , Lectina de Ligação a Manose/imunologia , Micobioma/imunologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Estudos de Casos e Controles , Ativação do Complemento , Complemento C3/deficiência , Complemento C3/imunologia , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
J Hand Surg Am ; 44(9): 728-741.e10, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31262534

RESUMO

PURPOSE: The purpose of the current review was to estimate failure rates of trapeziometacarpal (TMC) implants and compare against failure rates of nonimplant techniques for surgical treatment of TMC joint (basal thumb joint) arthritis. METHODS: A systematic review was conducted to identify articles reporting on thumb implant arthroplasty and on nonimplant arthroplasty techniques for treatment of base of thumb arthritis in the English literature. The collected data were combined to calculate failure rates per 100 procedure-years. Failure was defined by the requirement for a secondary salvage procedure. The failure rates between different implant and nonimplant arthroplasty groups were compared directly and implants with higher than anticipated failure rates were identified. RESULTS: One hundred twenty-five articles on implant arthroplasty and 33 articles on the outcome of nonimplant surgical arthroplasty of the TMC joint were included. The implant arthroplasty failure rates per 100 procedure-years were total joint replacement (2.4), hemiarthroplasty (2.5), interposition with partial trapezial resection (4.5), interposition with complete trapezial resection (1.7), and interposition with no trapezial resection (4.5). The nonimplant arthroplasty failure rates per 100 procedure-years were: trapeziectomy (0.49), joint fusion (0.52), and trapeziectomy with ligament reconstruction ± tendon interposition (0.23). CONCLUSIONS: Several implant designs (arthroplasties) had high rates of failure due to aseptic loosening, dislocation, and persisting pain. Furthermore, some implants had higher than anticipated failure rates than other implants within each class. Overall, the failure rates of nonimplant techniques were lower than those of implant arthroplasty. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

13.
Cancer Discov ; 9(9): 1288-1305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31266770

RESUMO

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαß+CD4-CD8-NK1.1- innate αß T cells (iαßT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαßTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαßTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαßTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαßT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαßT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαßTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαßTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαßTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.See related commentary by Banerjee et al., p. 1164.This article is highlighted in the In This Issue feature, p. 1143.

14.
Curr Opin Virol ; 37: 37-43, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177014

RESUMO

Although bacterial dysbiosis has been previously associated with carcinogenesis and HIV infection, the impact of the virome and these disease states has been less well studied. In this review, we will summarize what is known about the interplay between both the bacterial and the viral components of the microbiome on cancer and HIV pathogenesis. Bacterial dysbiosis has been associated with carcinogenesis such as colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer, breast cancer, and gastric cancer. The dysbiotic pathogenesis may be species-based or community-based and can have varying mechanisms of carcinogenesis. The human virome was also associated with certain cancers. Viruses, such as cytomegalovirus (CMV), Human herpesvirus 8 (HHV-8), human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV), all had associations with cancers. It was also reported that an altered bacteriophage community may lead to carcinogenesis by allowing opportunistic, oncogenic bacteria to proliferate in a gastrointestinal biofilm. This mechanism shows the importance of analyzing the bacteriome and the virome concurrently as their interactions can provide insight into new mechanisms in the pathogenesis of not only cancer, but other diseases as well. The enteric bacteriome was shown to be distinctly altered in immunocompromised HIV-infected individuals, and highly active antiretroviral therapy (HAART) was shown to at least partially reverse the alterations that HIV causes in the bacteriome. Studies have shown that the progression to HIV is associated with changes in the plasma concentration of commensal viruses. HIV also acts synergistically with multiple other viruses, such as HPV, EBV, varicella zoster virus (VZV), and HHV-8. Although it has been shown that HIV infection leads to enteric virome expansion in humans, most of the research on HIV's effect on the virome was conducted in non-human primates, and there is a lack of research on the effect of HAART on the virome. Virome-wide analysis is necessary for identifying novel viral etiologies. There is currently a wealth of information on the bacteriome and its associations with cancer and HIV, but more research should be conducted on the virome's associations and reaction to HAART as well as the bacteriome-virome interactions that may play a major role in pathogenesis and recovery.

15.
ACS Med Chem Lett ; 10(6): 857-862, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223438

RESUMO

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.

16.
J Virol ; 93(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31068430

RESUMO

The pathogenesis of Epstein-Barr virus (EBV) infection, including development of lymphomas and carcinomas, is dependent on the ability of the virus to transit from latency to the lytic phase. This conversion, and ultimately disease development, depends on the molecular switch protein, ZEBRA, a viral bZIP transcription factor that initiates transcription from promoters of viral lytic genes. By binding to the origin of viral replication, ZEBRA is also an essential replication protein. Here, we identified a novel DNA-binding motif of ZEBRA, N terminal to the canonical bZIP domain. This RRTRK motif is important for high-affinity binding to DNA and is essential for recognizing the methylation state of viral promoters. Mutations in this motif lead to deficiencies in DNA binding, recognition of DNA methylation, lytic cycle DNA replication, and viral late gene expression. This work advances our understanding of ZEBRA-dependent activation of the viral lytic cascade.IMPORTANCE The binding of ZEBRA to methylated and unmethylated viral DNA triggers activation of the EBV lytic cycle, leading to viral replication and, in some patients, cancer development. Our work thoroughly examines how ZEBRA uses a previously unrecognized basic motif to bind nonmethylated and methylated DNA targets, leading to viral lytic activation. Our findings show that two different positively charged motifs, including the canonical BZIP domain and a newly identified RRTRK motif, contribute to the mechanism of DNA recognition by a viral AP-1 protein. This work contributes to the assessment of ZEBRA as a potential therapeutic target for antiviral and oncolytic treatments.

17.
Clin Cancer Res ; 25(13): 3747-3749, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31072844

RESUMO

Patients with pancreatic ductal adenocarcinoma do not benefit from checkpoint blockade. However, human tumors harbor evidence of adaptive immunity in clonally expanded T-cell populations. Immune intact modeling of human tumors identifies stromal sequestration as a mechanism of immune escape. Targeting the stroma combined with checkpoint blockade unleashes antitumor immunity.See related article by Seo et al., p. 3934.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Imunidade Adaptativa , Humanos , Pâncreas , Linfócitos T
18.
Nat Commun ; 10(1): 1424, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926808

RESUMO

The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-ß, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.


Assuntos
Células Dendríticas/imunologia , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Neoplasias Pancreáticas/imunologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular , Progressão da Doença , Fatores de Transcrição Forkhead , Regulação Neoplásica da Expressão Gênica , Humanos , Lectinas Tipo C/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Transdução de Sinais , Células Th17/imunologia , Receptor 2 Toll-Like/metabolismo , Tretinoína/metabolismo
19.
Oncogene ; 38(23): 4512-4526, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30742098

RESUMO

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.


Assuntos
Cirrose Hepática/patologia , Células Mieloides/metabolismo , Transdução de Sinais , Quinase Syk/metabolismo , Animais , Carcinogênese , Carcinoma Hepatocelular/metabolismo , Transdiferenciação Celular , Cicloexilaminas/farmacologia , Feminino , Fibrose , Células Estreladas do Fígado/citologia , Humanos , Interleucina-8/metabolismo , Lectinas Tipo C/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais , Fosforilação Oxidativa , Fenótipo , Pirimidinas/farmacologia , Receptores de Superfície Celular/metabolismo , Estilbenos/farmacologia , Quinase Syk/antagonistas & inibidores , Transcriptoma
20.
Gastroenterology ; 156(7): 2097-2115.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30768986

RESUMO

Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The "germ theory of cancer" was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.


Assuntos
Bactérias/imunologia , Imunoterapia/métodos , Microbiota/imunologia , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/terapia , Imunidade Adaptativa , Animais , Bactérias/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Microbiota/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Evasão Tumoral , Microambiente Tumoral
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