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1.
ACS Infect Dis ; 8(11): 2348-2361, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36219583

RESUMO

Better understanding of the molecular mechanisms underlying COVID-19 severity is desperately needed in current times. Although hyper-inflammation drives severe COVID-19, precise mechanisms triggering this cascade and what role glycosylation might play therein are unknown. Here we report the first high-throughput glycomic analysis of COVID-19 plasma samples and autopsy tissues. We find that α2,6-sialylation is upregulated in the plasma of patients with severe COVID-19 and in autopsied lung tissue. This glycan motif is enriched on members of the complement cascade (e.g., C5, C9), which show higher levels of sialylation in severe COVID-19. In the lung tissue, we observe increased complement deposition, associated with elevated α2,6-sialylation levels, corresponding to elevated markers of poor prognosis (IL-6) and fibrotic response. We also observe upregulation of the α2,6-sialylation enzyme ST6GAL1 in patients who succumbed to COVID-19. Our work identifies a heretofore undescribed relationship between sialylation and complement in severe COVID-19, potentially informing future therapeutic development.


Assuntos
COVID-19 , Humanos , Glicosilação , Polissacarídeos
2.
Cancer Cell ; 40(7): 720-737.e5, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35660135

RESUMO

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.


Assuntos
Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Receptores de Interleucina-15/metabolismo , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Interleucina-15/metabolismo , Interleucina-15/farmacologia , Interleucina-15/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Microambiente Tumoral , Neoplasias Pancreáticas
3.
medRxiv ; 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35702159

RESUMO

Better understanding of the mechanisms of COVID-19 severity is desperately needed in current times. Although hyper-inflammation drives severe COVID-19, precise mechanisms triggering this cascade and what role glycosylation might play therein is unknown. Here we report the first high-throughput glycomic analysis of COVID-19 plasma samples and autopsy tissues. We find α2,6-sialylation is upregulated in plasma of patients with severe COVID-19 and in the lung. This glycan motif is enriched on members of the complement cascade, which show higher levels of sialylation in severe COVID-19. In the lung tissue, we observe increased complement deposition, associated with elevated α2,6-sialylation levels, corresponding to elevated markers of poor prognosis (IL-6) and fibrotic response. We also observe upregulation of the α2,6-sialylation enzyme ST6GAL1 in patients who succumbed to COVID-19. Our work identifies a heretofore undescribed relationship between sialylation and complement in severe COVID-19, potentially informing future therapeutic development.

4.
Cell ; 185(1): 169-183.e19, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34963055

RESUMO

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Interferon Tipo I/metabolismo , Neoplasias Pulmonares/imunologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Reparo de DNA por Recombinação/genética , Proteínas Repressoras/metabolismo , Evasão Tumoral/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunidade Inata/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Mol Cell Proteomics ; 20: 100160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34634466

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Glycans, such as carbohydrate antigen 19-9, are biomarkers of PDAC and are emerging as important modulators of cancer phenotypes. Herein, we used a systems-based approach integrating glycomic analysis of the well-established KC mouse, which models early events in transformation, and analysis of samples from human pancreatic cancer patients to identify glycans with potential roles in cancer formation. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3-sialic acid and α-2,6-sialic acid, bisecting GlcNAc and poly-N-acetyllactosamine. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes are observed in the KC mouse model. In silico analysis of bulk and single-cell sequencing data identified ST6 beta-galactoside alpha-2,6-sialyltransferase 1, which underlies α-2,6-sialic acid, as overexpressed in human PDAC, concordant with histological data showing higher levels of this enzyme at the earliest stages. To test whether ST6 beta-galactoside alpha-2,6-sialyltransferase 1 promotes pancreatic cancer, we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. The analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Polissacarídeos/metabolismo , Sialiltransferases/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Glicosilação , Humanos , Masculino , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Proteoma , Sialiltransferases/genética , Análise de Sistemas , beta-D-Galactosídeo alfa 2-6-Sialiltransferase
6.
Cell Rep ; 36(8): 109578, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433022

RESUMO

Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53R172H mutation with their p53 wild-type control. KrasG12D/+;Trp53R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment of CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR KrasG12D/+;Trp53R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.


Assuntos
Carcinoma Ductal Pancreático , Mutação com Ganho de Função , Imunoterapia , Infiltração de Neutrófilos/genética , Neutrófilos/imunologia , Neoplasias Pancreáticas , Proteína Supressora de Tumor p53 , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Células Th1 , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
8.
Nat Cell Biol ; 22(9): 1130-1142, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839549

RESUMO

Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.


Assuntos
Epigênese Genética/genética , Transição Epitelial-Mesenquimal/genética , Proteínas F-Box/genética , Inativação Gênica/fisiologia , Metástase Neoplásica/genética , Subunidades Proteicas/genética , Quinases da Família src/genética , Animais , Linhagem Celular , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Células PC-3 , Transdução de Sinais/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética
9.
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
10.
Hepatology ; 71(2): 477-494, 2020 02.
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.


Assuntos
Imunidade Adaptativa/fisiologia , Fígado Gorduroso/etiologia , Imunidade Inata/fisiologia , Linfócitos Intraepiteliais/fisiologia , Animais , Feminino , Masculino , Camundongos
11.
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.
Cancer Discov ; 9(9): 1288-1305, 2019 09.
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.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Macrófagos/imunologia , Neoplasias Pancreáticas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/imunologia , Animais , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade Inata , Imunoterapia Adotiva , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Pancreáticas/terapia , Linfócitos T/transplante , Microambiente Tumoral
13.
Ann Surg Oncol ; 26(11): 3472-3477, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31147991

RESUMO

BACKGROUND: Mammographic breast density (MBD) is an independent risk factor for breast cancer. Information regarding the relationship of MBD and breast cancer biology in women with ductal carcinoma in situ (DCIS) is currently lacking. This study aimed to examine the clinicopathologic characteristics of DCIS in women stratified by MBD. METHODS: A retrospective review was performed to identify women with pure DCIS who underwent preoperative mammography between 2010 and 2018. Clinicopathologic and demographic data were collected. For the purpose of analysis, MBD was categorized as "non-dense" (Breast Imaging-Reporting and Data System [BI-RADS] density categories A and B) or "dense" (BI-RADS C and D) according to its identification in radiology reports. RESULTS: Of 3227 patients with a breast cancer diagnosis enrolled in the institutional Breast Cancer Database during the study period, 658 (20%) had pure DCIS. Of these 658 patients, 42% had non-dense breasts, and 58% had dense breasts. Most lesions were non-palpable (92%) and detected by mammography (84%). Patients with dense breasts were more likely to be younger at the time of diagnosis (p < 0.001), premenopausal (p < 0.001), and Asian (p = 0.018), and to have higher-grade disease (p = 0.006; Table 2). Family history, BRCA status, parity, mammogram frequency, palpability, method of presentation, lesion size, hormone receptor status, comedo histology, and recurrence did not differ significantly between the two groups (Table 1). The median follow-up period was 7.1 years. CONCLUSION: Women with pure DCIS and higher MBD are more likely to be younger at the time of diagnosis, premenopausal, and Asian, and to present with higher-grade disease. Further research on the relationship of age, MBD, and tumor biology in DCIS is warranted.


Assuntos
Densidade da Mama , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Mamografia/métodos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Ultrassonografia Mamária/métodos
14.
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 , Neoplasias Pancreáticas
15.
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 , Receptor de Manose , 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
16.
Cancer Cell ; 34(5): 757-774.e7, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30423296

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Tolerância Imunológica/imunologia , Macrófagos/imunologia , Neoplasias Pancreáticas/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica/genética , Células L , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Transcrição STAT1/metabolismo , Células Th1/citologia , Células Th17/citologia
17.
Cancer Discov ; 8(4): 403-416, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29567829

RESUMO

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.


Assuntos
Carcinogênese , Microbiota , Monócitos/fisiologia , Neoplasias Pancreáticas/microbiologia , Receptores Toll-Like/metabolismo , Animais , Bactérias , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Transdução de Sinais
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