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1.
Cell ; 174(1): 88-101.e16, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29909986

RESUMO

In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/ß-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.


Assuntos
Imunidade Adaptativa , Mitofagia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Azoximetano/toxicidade , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Permeabilidade da Membrana Celular , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Compostos Ferrosos/metabolismo , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mitofagia/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Taxa de Sobrevida
2.
Nature ; 513(7519): 564-568, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25043027

RESUMO

FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-ß1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.


Assuntos
Interleucinas/imunologia , Intestinos/citologia , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Colite/imunologia , Colite/patologia , Colo/citologia , Colo/imunologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Imunidade nas Mucosas , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-23/imunologia , Interleucina-33 , Interleucinas/antagonistas & inibidores , Interleucinas/metabolismo , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia , Timo/citologia , Fator de Crescimento Transformador beta/metabolismo
3.
Semin Immunol ; 25(5): 352-7, 2013 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-24184013

RESUMO

The intestine represents one of the most challenging sites for the immune system as immune cells must be able to mount an efficient response to invading pathogens while tolerating the large number and diverse array of resident commensal bacteria. Foxp3(+) regulatory T-cells (Tregs) play a non-redundant role at maintaining this balance. At the same time Treg cell differentiation and function can be modulated by the intestinal microbiota. In this review, we will discuss effector mechanisms of Treg cells in the intestine and how these cells can be influenced by the intestinal microbiota.


Assuntos
Bactérias/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Linfócitos T Reguladores/imunologia , Animais , Homeostase , Humanos , Microbiota/imunologia , Timo/imunologia
4.
Cancer Discov ; 13(10): 2192-2211, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37489084

RESUMO

In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived tumor organoids (PDTO) show enormous potential for preclinical testing; however, cultured tumor cells lose important characteristics, including the consensus molecular subtypes (CMS). To better reflect the cellular heterogeneity, we established the colorectal cancer organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAF) from 30 patients. Context-specific phenotyping showed that xenotransplantation or coculture with CAFs improves the transcriptomic fidelity and instructs subtype-specific stromal gene expression. Furthermore, functional profiling in coculture exposed CMS4-specific therapeutic resistance to gefitinib and SN-38 and prognostic expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as a common target. Our results demonstrate that colorectal cancer phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for a faithful representation of molecular subtypes and therapy responses ex vivo. SIGNIFICANCE: Systematic characterization of the organoid-stroma biobank provides a resource for context dependency in colorectal cancer. We demonstrate a colorectal cancer subtype memory of PDTOs that is independent of specific driver mutations. Our data underscore the importance of functional profiling in cocultures for improved preclinical testing and identification of stromal resistance mechanisms. This article is featured in Selected Articles from This Issue, p. 2109.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Humanos , Bancos de Espécimes Biológicos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Células Tumorais Cultivadas , Fibroblastos Associados a Câncer/metabolismo , Organoides/patologia , Microambiente Tumoral/genética
5.
EMBO Rep ; 10(12): 1314-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19893576

RESUMO

Our understanding of the molecular mechanisms that link inflammation and cancer has significantly increased in recent years. Here, we analyse genetic evidence indicating that the transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) have a central role in this context by regulating distinct functions in cancer cells and surrounding non-tumorigenic cells. In immune cells, NF-kappaB induces the transcription of genes that encode pro-inflammatory cytokines, which can act in a paracrine manner on initiated cells. By contrast, in tumorigenic cells, both NF-kappaB and STAT3 control apoptosis, and STAT3 can also enhance proliferation. Consequently, inflammation should be considered as a valuable target for cancer prevention and therapy.


Assuntos
Quinase I-kappa B/fisiologia , Inflamação/fisiopatologia , NF-kappa B/fisiologia , Neoplasias/etiologia , Neoplasias/patologia , Fator de Transcrição STAT3/fisiologia , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Inflamação/patologia , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/metabolismo , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
6.
ISME J ; 14(3): 879, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31748709

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
ISME J ; 10(10): 2389-404, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27003245

RESUMO

The gut microbiome is significantly altered in inflammatory bowel diseases, but the basis of these changes is not well understood. We have combined metagenomic and metatranscriptomic profiling of the gut microbiome to assess modifications to both bacterial community structure and transcriptional activity in a mouse model of colitis. By using transcriptomic analysis of colonic tissue and luminal RNA derived from the host, we have also characterised how host transcription relates to the microbial transcriptional response in inflammation. In colitis, increased abundance and transcription of diverse microbial gene families involved in responses to nutrient deprivation, antimicrobial peptide production and oxidative stress support an adaptation of multiple commensal genera to withstand a diverse set of environmental stressors in the inflammatory environment. These data are supported by a transcriptional signature of activated macrophages and granulocytes in the gut lumen during colitis, a signature that includes the transcription of the key antimicrobial genes S100a8 and S100a9 (calprotectin). Genes involved in microbial resistance to oxidative stress, including Dps/ferritin, Fe-dependent peroxidase and glutathione S-transferase were identified as changing to a greater extent at the level of transcription than would be predicted by DNA abundance changes, implicating a role for increased oxygen tension and/or host-derived reactive oxygen species in driving transcriptional changes in commensal microbes.


Assuntos
Bactérias/genética , Colite/genética , Colite/microbiologia , Microbioma Gastrointestinal , Animais , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Colite/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Metagenômica , Camundongos , Camundongos Endogâmicos C57BL
9.
Cell Rep ; 7(6): 1914-25, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24882009

RESUMO

The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.


Assuntos
Carcinogênese/metabolismo , Quinase I-kappa B/metabolismo , Intestinos/imunologia , Células Matadoras Naturais/patologia , Células Mieloides/citologia , Células Mieloides/enzimologia , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/patologia , Carcinogênese/patologia , Polaridade Celular , Transformação Celular Neoplásica , Células HEK293 , Humanos , Células Matadoras Naturais/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/patologia , Fosforilação , Transdução de Sinais
10.
Cancer Cell ; 15(2): 91-102, 2009 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-19185844

RESUMO

Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.


Assuntos
Ciclo Celular/fisiologia , Sobrevivência Celular/fisiologia , Colite , Receptor gp130 de Citocina/metabolismo , Enterócitos/fisiologia , Neoplasias , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/fisiologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Colite/complicações , Colite/imunologia , Colite/patologia , Receptor gp130 de Citocina/genética , Enterócitos/citologia , Enterócitos/patologia , Humanos , Inflamação/imunologia , Interleucina-11/imunologia , Interleucina-6/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos , Neoplasias/etiologia , Neoplasias/imunologia , Neoplasias/patologia , Regeneração/fisiologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia
12.
Cell ; 130(5): 918-31, 2007 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-17803913

RESUMO

IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.


Assuntos
Quinase I-kappa B/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , NF-kappa B/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Choque Séptico/metabolismo , Animais , Apoptose , Carbolinas/farmacologia , Caspase 1/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Neutrófilos/imunologia , Neutrófilos/patologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/metabolismo , Serina Endopeptidases/metabolismo , Serpinas/metabolismo , Choque Séptico/induzido quimicamente , Choque Séptico/enzimologia , Choque Séptico/imunologia , Choque Séptico/patologia , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa/sangue
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