RESUMO
Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.
Assuntos
Células Matadoras Naturais , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Macrófagos , Células Mieloides , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genéticaRESUMO
In this issue of Immunity, Chow et al. (2019) show that the CXCR3-CXCL9 axis is required for reinvigoration of intratumoral CD8+ T cell responses in response to PD-1 blockade and demonstrate that local guidance to dendritic cells, rather than recruitment of T cells into the tumor, underlies the importance of this chemokine axis.
Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Quimiocina CXCL10 , Quimiocina CXCL9 , Células Dendríticas , Humanos , Receptores CXCR3 , Linfócitos TRESUMO
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1ß (IL-1ß) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
Assuntos
Proteínas de Transporte/imunologia , Diferenciação Celular/imunologia , Células Th2/imunologia , Transativadores/imunologia , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células NIH 3T3 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th2/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
Generation of functional CD8 + T cell memory typically requires engagement of CD4 + T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (T E ) and subsequent memory (T M ) CD8 + T cell formation appear impervious to a lack of CD4 + T cell help during priming. Nonetheless, such "helpless" CD8 + T M respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 + T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8 + T E differentiation is largely normal but a multiplicity of helpless CD8 T M defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8 + T M potential and recall capacity. Our findings provide a unified explanation for helpless CD8 + T cell memory and emphasize an unexpected CD8 + T M plasticity with implications for vaccination strategies and beyond.
RESUMO
During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.
Assuntos
Antígenos CD28 , Fator 1 de Transcrição de Linfócitos T , Fator 1 de Transcrição de Linfócitos T/genética , Receptor de Morte Celular Programada 1 , Linfócitos T CD8-Positivos , Diferenciação Celular , Fatores de TranscriçãoRESUMO
MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.
Assuntos
Fibroblastos Associados a Câncer , Histonas , Melanoma , Animais , Camundongos , Cromatina/genética , Expressão Gênica , Histonas/genética , Melanoma/genética , Microambiente Tumoral/genéticaRESUMO
Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+ T helper cells ("CXCL13+ TH") and Granzyme K+ PD-1+ effector-like CD8+ T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+ T cells dominated in nonresponders. CD4+ and CD8+ T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+ (Progenitor-exhausted) CD8+ T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+ T cell differentiation occurs upon ICB. We found that these Progenitor CD8+ T cells interact with CXCL13+ TH within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ TH control the differentiation of tumor-specific Progenitor exhasuted CD8+ T cells following ICB.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Linfócitos T CD8-Positivos , Neoplasias Hepáticas/patologia , Receptor de Morte Celular Programada 1 , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Células Dendríticas/patologiaRESUMO
Chronic antigen stimulation leads to T cell exhaustion. Nutrient restrictions and other suppressive factors in the tumor microenvironment further exacerbate T cell dysfunction. Better understanding of heterogeneity and dynamics of exhausted CD8 T cells will guide novel therapies that modulate T cell differentiation to achieve more effective antitumor responses.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Ativação Linfocitária , Microambiente Tumoral , Diferenciação CelularRESUMO
T follicular helper (Tfh) cells are a subset of CD4+ T cells essential in immunity and have a role in helping B cells produce antibodies against pathogens. However, their role during cancer progression remains unknown. The mechanism of action of Tfh cells remains elusive because contradictory data have been reported on their protumor or antitumor responses in human and murine tumors. Like Tfh cells, Th2 cells are also involved in humoral immunity and are regularly associated with tumor progression and poor prognosis, mainly through their secretion of IL4. Here, we showed that Tfh cells expressed hematopoietic prostaglandin D2 (PGD2) synthase in a pSTAT1/pSTAT3-dependent manner. Tfh cells produced PGD2, which led to recruitment of Th2 cells via the PGD2 receptor chemoattractant receptor homologous molecule expressed on Th type 2 cells (CRTH2) and increased their effector functions. This cross-talk between Tfh and Th2 cells promoted IL4-dependent tumor growth. Correlation between Th2 cells, Tfh cells, and hematopoietic PGD2 synthase was observed in different human cancers and associated with outcome. This study provides evidence that Tfh/Th2 cross-talk through PGD2 limits the antitumor effects of Tfh cells and, therefore, could serve as a therapeutic target.
Assuntos
Interleucina-4 , Prostaglandina D2 , Animais , Comunicação Celular , Humanos , Oxirredutases Intramoleculares , Lipocalinas , Camundongos , Prostaglandina D2/farmacologiaRESUMO
Lossoffunction BRCA mutations are frequent in highgrade serous ovarian carcinoma. BRCA1 and 2 mutations lead to homologous recombination (HR) deficiency. Poly(ADPribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of highgrade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCAmutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified de novo TP53 mutations, as well as increased frequencies of preexisting TP53 mutations compared with the primary tumor. In HCT116 TP53/ cells carrying BRCA2 pathogenic mutations, TP53 inactivating mutations were associated with lower sensitivity to olaparib in vitro. Thus, inactivating TP53 mutations may be associated to olaparib resistance in the presence of BRCA mutations. In conclusion, the present findings demonstrated resistance to PARPi with de novo TP53 mutations that may be clinically relevant. As TP53 mutations are easily detectable with targeted nextgeneration sequencing panels, these may serve as surrogate markers for the onset of PARPi resistance in the context of routine patient management strategies.
Assuntos
Proteína BRCA1/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação com Perda de Função , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Idoso , Proteína BRCA1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Células HCT116 , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Poli(ADP-Ribose) Polimerases/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the TME, via a TGFß-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor (splicing factor, proline- and glutamine-rich) was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the Il12rb1 promoter, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the TME, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.
Assuntos
Fator Regulador 1 de Interferon/genética , Interferon gama/metabolismo , Neoplasias/imunologia , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/patologia , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Precursores de RNA/metabolismo , RNA Mensageiro/metabolismo , RNA-Seq , Receptores de Interleucina-12 , Células Th1/imunologia , Células Th1/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Understanding the basis of cellular differentiation is a fundamental issue in developmental biology but also for the comprehension of pathological processes. In fact, the palette of developmental decisions for naive CD4 T cells is a critical aspect of the development of appropriate immune responses which could control infectious processes or cancer growth. However, the current accumulation of data on CD4 T cells biology reveals a complex world with different helper populations. Naive CD4 T cells can differentiate into different subtypes in response to cytokine stimulation. This stimulation involves a complex transcriptional network implicating the activation of Signal Transducer and Activator of Transcription but also master regulator transcription factors allowing the functions of each helper T lymphocyte subtype. In this review, we will present an overview of the transcriptional regulation which controls process of helper T cells differentiation. We will focus on the role of initiator transcriptional factors and on master regulators but also on other nonspecific transcriptional factors which refine the T helper polarization to stabilize or modulate the differentiation program.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Fatores de Transcrição/metabolismo , Transcrição Gênica , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Regulação da Expressão Gênica , HumanosRESUMO
Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8+ T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/prevenção & controle , Resistencia a Medicamentos Antineoplásicos , Lipídeos/química , Animais , Linfócitos T CD8-Positivos/citologia , Caspases/metabolismo , Morte Celular , Linhagem Celular Tumoral , Feminino , Fluoruracila/farmacologia , Homeostase , Humanos , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Fenótipo , Fosfatidilcolinas/química , Triglicerídeos/químicaRESUMO
CD4+ T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans among other responses. The biology of CD4+ T cells is complex because naïve CD4+ T cells can differentiate into various subpopulations with various functions that depend on the milieu. Recently, a new population of IL-9-secreting T cells called Th9 cells has been described. These cells are characterized by their ability to produce IL-9. These cells were described to be involved in parasite infections and allergic inflammation. However, some reports described their presence in the tumor bed in mice and humans. Molecular events that account for Th9 effector properties and differentiation are still elusive. To study these mechanisms, downregulation of gene expression and protein-DNA interaction detection allow to identify and study putative transcription factors regulating gene expression during their differentiation. Here, we describe three methods allowing the study of transcription factors in Th9 cells: siRNA transfection for downregulation of gene expression, and chromatin immunoprecipitation and liquid luminescent DNA precipitation assay to detect protein-DNA interactions.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imunoprecipitação da Cromatina , Humanos , Interleucina-9/metabolismo , Camundongos , Ligação Proteica/genética , Ligação Proteica/fisiologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/genéticaRESUMO
IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of TH9 cells. TH9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, TH9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human TH9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of TH9 cells and their possible clinical relevance for cancer immunotherapy.
Assuntos
Imunidade , Interleucina-9/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Imunidade Adaptativa , Animais , Citocinas/genética , Citocinas/metabolismo , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Imunomodulação , Interleucina-9/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/genética , Transdução de SinaisRESUMO
Sirtuin-1 deacetylates proteins and has emerged as a critical regulator of different cellular processes, particularly inflammation. Basal SIRT1 activity was previously found to limit Th9 and enhance Th17 differentiation in mice, but the effect of pharmacological SIRT1 activation on T cell differentiation and antitumor responses remains unclear. Here, we find that SIRT1 pharmacological agonists selectively impede mouse and human Th17 cell differentiation. SIRT1 activation induces STAT3 deacetylation, thus reducing its ability to translocate into the nucleus, bind to Rorc promoter, and induce its transcription. SIRT1 agonists reduce tumor growth in mice by blocking Th17 cell differentiation. In cancer patients, the SIRT1 agonist metformin reduced the frequency of Th17 cells and STAT3 acetylation levels. Altogether, these data underscore that SIRT1 activation impedes Th17 cell differentiation and thereby limits tumor growth and suggest that SIRT1 activators may directly target IL-17A functions.
Assuntos
Fator de Transcrição STAT3/metabolismo , Sirtuína 1/metabolismo , Acetilação/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Carbazóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/agonistas , Sirtuína 1/química , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Transplante HeterólogoRESUMO
TRAIL induces selective tumor cell death through TRAIL-R1 and TRAIL-R2. Despite the fact that these receptors share high structural homologies, induction of apoptosis upon ER stress, cell autonomous motility and invasion have solely been described to occur through TRAIL-R2. Using the TALEN gene-editing approach, we show that TRAIL-R1 can also induce apoptosis during unresolved unfolded protein response (UPR). Likewise, TRAIL-R1 was found to co-immunoprecipitate with FADD and caspase-8 during ER stress. Its deficiency conferred resistance to apoptosis induced by thaspigargin, tunicamycin or brefeldin A. Our data also demonstrate that tumor cell motility and invasion-induced by TRAIL-R2 is not cell autonomous but induced in a TRAIL-dependant manner. TRAIL-R1, on the other hand, is unable to trigger cell migration owing to its inability to induce an increase in calcium flux. Importantly, all the isogenic cell lines generated in this study revealed that apoptosis induced TRAIL is preferentially induced by TRAIL-R1. Taken together, our results provide novel insights into the physiological functions of TRAIL-R1 and TRAIL-R2 and suggest that targeting TRAIL-R1 for anticancer therapy is likely to be more appropriate owing to its lack of pro-motile signaling capability.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Caspase 8/metabolismo , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Cricetulus , Relação Dose-Resposta a Droga , Proteína de Domínio de Morte Associada a Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , TransfecçãoRESUMO
Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy.