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1.
bioRxiv ; 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39372744

RESUMO

Despite the promising results of immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance mechanisms has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that recapitulate the disparate responses to ICB seen in patients. We demonstrate that these models capture the cellular and molecular complexity of human disease and reveal key factors shaping the tumor microenvironment and influencing ICB response. BR1-responsive tumor cells express inflammatory programs that polarize microglia into reactive states, eliciting robust T cell recruitment. In contrast, BR3-resistant melanoma cells are enriched in neurological programs and exploit tolerance mechanisms to maintain microglia homeostasis and limit T cell infiltration. In humans, BR1 and BR3 expression signatures correlate positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study provides clinically relevant models and uncovers mechanistic insights into BrM ICB responses, offering potential biomarkers and therapeutic targets to improve therapy efficacy.

2.
Cell ; 184(21): 5338-5356.e21, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34624222

RESUMO

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.


Assuntos
Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Microbiota , Monócitos/metabolismo , Microambiente Tumoral , Akkermansia/efeitos dos fármacos , Akkermansia/fisiologia , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Fibras na Dieta/farmacologia , Fosfatos de Dinucleosídeos/administração & dosagem , Fosfatos de Dinucleosídeos/farmacologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Fagócitos/metabolismo , Transcrição Gênica/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
4.
Nat Med ; 26(5): 781-791, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284588

RESUMO

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais , Imunoterapia , Melanoma/patologia , Melanoma/terapia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterogeneidade Genética , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/diagnóstico , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Resultado do Tratamento , Sequenciamento Completo do Genoma
5.
Methods Enzymol ; 632: 309-337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32000903

RESUMO

The tumor microenvironment (TME) is a highly complex and dynamic ensemble of cells of which a variety of immune cells are a major component. The unparalleled results obtained with immunotherapeutic approaches have underscored the importance of examining the immune landscape of the TME. Recent technological advances have incorporated high-throughput techniques at the single cell level, such as single cell RNA sequencing, mass cytometry, and multi-parametric flow cytometry to the characterization of the TME. Among them, flow cytometry is the most broadly used both in research and clinical settings and multi-color analysis is now routinely performed. The high dimensionality of the data makes the traditional manual gating strategy in 2D scatter plots very difficult. New unbiased visualization techniques provide a solution to this problem. Here we describe the steps to characterize the immune cell compartment in the TME in mouse tumor models by high-parametric flow cytometry, from the experimental setup to the analysis methodology with special emphasis on the use of unsupervised algorithms.


Assuntos
Citometria de Fluxo/métodos , Sistema Imunitário/citologia , Neoplasias/imunologia , Microambiente Tumoral , Algoritmos , Animais , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Análise por Conglomerados , Sistema Imunitário/imunologia , Camundongos
6.
J Immunol ; 200(3): 1008-1015, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29282306

RESUMO

NK cells play important roles during immunosurveillance against tumors and viruses as they trigger cytotoxicity against susceptible cells and secrete proinflammatory cytokines such as IFN-γ. In addition, upon activation, macrophages can become proinflammatory (M1) or anti-inflammatory (M2) cells. Although the consequences of the cross-talk between M1 and NK cells are known, the outcome of the cross-talk between M2 and NK cells remains ill-defined. Therefore, in the current work, we investigated the outcome and the underlying mechanisms of the interaction between resting or stimulated human NK cells with M1 or M2. We observed a lower percentage of activated NK cells that produced less IFN-γ upon coculture with M2. Also, CD56dim NK cells cocultured with M2 displayed lower degranulation and cytotoxic activity than NK cells cocultured with M1. Soluble TGF-ß and M2-driven upregulation of CD85j (ILT-2) on NK cells accounted for the diminished IFN-γ production by CD56bright NK cells, whereas M2-driven upregulation of CD85j on NK cells accounted for the generation of hyporesponsive CD56dim NK cells with limited degranulation and cytotoxic capacity. Accordingly, M2 expressed higher amounts of HLA-G, the main ligand for CD85j, than M1. Hyporesponsiveness to degranulation in NK cells was not restored at least for several hours upon removal of M2. Therefore, alternatively activated macrophages restrain NK cell activation and effector functions through different mechanisms, leading to NK cells that display diminished IFN-γ production and at least a transiently impaired degranulation ability. These results unravel an inhibitory circuit of possible relevance in pathological situations.


Assuntos
Comunicação Celular/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Ativação de Macrófagos/imunologia , Fator de Crescimento Transformador beta/metabolismo , Antígenos CD/imunologia , Antígeno CD56/metabolismo , Células Cultivadas , Técnicas de Cocultura , Antígenos HLA-G/metabolismo , Humanos , Interferon gama/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Macrófagos/imunologia , Fator de Crescimento Transformador beta/imunologia
7.
Cancer Cell ; 31(2): 161-163, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28196588

RESUMO

Type I interferons have been shown to play a major role in anti-cancer immunity. In this issue of Cancer Cell, Katlinski et al. describe tumor-induced degradation of type I interferon receptor IFNAR1 chain as a new immune-evasion mechanism in colorectal cancers. Stabilizing IFNAR1 inhibits tumor growth and improves immunotherapy efficacy.


Assuntos
Interferon Tipo I/metabolismo , Evasão Tumoral , Humanos
8.
Immunity ; 45(4): 714-716, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760335

RESUMO

It has recently become apparent that the gut microbiota modulates the response to cancer therapy. In this issue of Immunity, Daillère et al. (2016) identified two bacterial species potentiating the anti-tumor effect of cyclophosphamide that are kept in check by the sensor NOD2.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal/fisiologia , Neoplasias/microbiologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico
9.
J Immunol ; 197(3): 953-61, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27342842

RESUMO

Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8(+) T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell-depleted mice exhibited a significantly higher frequency of SIY-specific CD8(+) T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8(+) T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell-depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8(+) T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Neoplasias Experimentais/imunologia , Animais , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Separação Celular , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/imunologia
10.
Am J Physiol Gastrointest Liver Physiol ; 311(1): G40-9, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27151946

RESUMO

Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Innate immunity contributes to the pathogenesis of CD, but the mechanisms remain poorly understood. Although previous in vitro work suggests that gliadin peptide p31-43 acts as an innate immune trigger, the underlying pathways are unclear and have not been explored in vivo. Here we show that intraluminal delivery of p31-43 induces morphological changes in the small intestinal mucosa of normal mice consistent with those seen in CD, including increased cell death and expression of inflammatory mediators. The effects of p31-43 were dependent on MyD88 and type I IFNs, but not Toll-like receptor 4 (TLR4), and were enhanced by coadministration of the TLR3 agonist polyinosinic:polycytidylic acid. Together, these results indicate that gliadin peptide p31-43 activates the innate immune pathways in vivo, such as IFN-dependent inflammation, relevant to CD. Our findings also suggest a common mechanism for the potential interaction between dietary gluten and viral infections in the pathogenesis of CD.


Assuntos
Doença Celíaca/imunologia , Gliadina/toxicidade , Imunidade Inata/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Regulação da Expressão Gênica , Genótipo , Gliadina/administração & dosagem , Mediadores da Inflamação/metabolismo , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Fenótipo , Poli I-C/farmacologia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/metabolismo
11.
PLoS One ; 9(6): e99236, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24915573

RESUMO

Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNß and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.


Assuntos
Progressão da Doença , Gliadina/administração & dosagem , Gliadina/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/patologia , Poli I-C/administração & dosagem , Poli I-C/efeitos adversos , Administração Oral , Animais , Citocinas/sangue , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Helicase IFIH1 Induzida por Interferon , Enteropatias/sangue , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo
12.
PLoS One ; 9(2): e89068, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586509

RESUMO

Lymphocytic infiltration in the lamina propria (LP), which is primarily composed of CD4(+) Th1 cells and plasma cells, and increased numbers of intraepithelial lymphocytes (IELs), is a characteristic finding in active celiac disease (CD). Signals for this selective cell recruitment have not been fully established. CXCR3 and its ligands, particularly CXCL10, have been suggested to be one of the most relevant pathways in the attraction of cells into inflamed tissues. In addition, CXCR3 is characteristically expressed by Th1 cells. The aim of this work was to investigate the participation of the chemokine CXCL10/CXCR3 axis in CD pathogenesis. A higher concentration of CXCL10 was found in the serum of untreated CD patients. The mRNA levels of CXCL10 and CXCL11 but not CXCL9 were significantly higher in duodenal biopsies from untreated CD patients compared with non-CD controls or treated patients. The results demonstrate that CXCL10 is abundantly produced in untreated CD and reduced in treated patients, and the expression of CXCL10 was found to be correlated with the IFNγ levels in the tissue. Plasma cells and enterocytes were identified as CXCL10-producing cells. Moreover, the CXCL10 expression in intestinal tissues was upregulated by poly I:C and IL-15. IELs, LP T lymphocytes, and plasma cells, which infiltrate the intestinal mucosa in untreated CD, express CXCR3. The CXCR3/CXCL10 signalling axis is overactivated in the small intestinal mucosa in untreated patients, and this finding explains the specific recruitment of the major cell populations that infiltrate the epithelium and the LP in CD.


Assuntos
Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Quimiocina CXCL10/metabolismo , Intestino Delgado/imunologia , Plasmócitos/imunologia , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Adulto , Doença Celíaca/sangue , Doença Celíaca/patologia , Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/sangue , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Criança , Regulação da Expressão Gênica/imunologia , Humanos , Interferon beta/metabolismo , Interferon gama/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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