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Nature ; 568(7751): E3, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30911170


In this Letter, a citation to 'Fig. 1e' has been corrected to 'Fig. 1d' in the sentence starting "By contrast, the anti-tumour response…". This has been corrected online.

Nature ; 566(7743): 270-274, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728504


There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N6-methyadenosine (m6A) methylation through the m6A-binding protein YTHDF15. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8+ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8+ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m6A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1-/- mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy.

Adenosina/análogos & derivados , Adenosina/metabolismo , Células Dendríticas/imunologia , Neoplasias/imunologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/metabolismo , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Catepsinas/antagonistas & inibidores , Catepsinas/biossíntese , Catepsinas/genética , Apresentação Cruzada/imunologia , Células Dendríticas/enzimologia , Feminino , Humanos , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Biossíntese de Proteínas , Proteínas/genética , RNA Mensageiro/química , Proteínas de Ligação a RNA/genética , Transcriptoma/genética
Immunity ; 47(2): 363-373.e5, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28801234


Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.

Antígenos de Diferenciação/metabolismo , Neoplasias do Colo/imunologia , DNA Mitocondrial/imunologia , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Animais , Anticorpos Bloqueadores/uso terapêutico , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Células Cultivadas , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Apresentação Cruzada , Modelos Animais de Doenças , Humanos , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Evasão Tumoral
Mol Cell ; 63(4): 711-719, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27477909


We present a highly sensitive and selective chemical labeling and capture approach for genome-wide profiling of 5-hydroxylmethylcytosine (5hmC) using DNA isolated from ∼1,000 cells (nano-hmC-Seal). Using this technology, we assessed 5hmC occupancy and dynamics across different stages of hematopoietic differentiation. Nano-hmC-Seal profiling of purified Tet2-mutant acute myeloid leukemia (AML) murine stem cells allowed us to identify leukemia-specific, differentially hydroxymethylated regions that harbor known and candidate disease-specific target genes with differential 5hmC peaks compared to normal stem cells. The change of 5hmC patterns in AML strongly correlates with differential gene expression, demonstrating the importance of dynamic alterations of 5hmC in regulating transcription in AML. Together, covalent 5hmC labeling offers an effective approach to study and detect DNA methylation dynamics in in vivo disease models and in limited clinical samples.

5-Metilcitosina/análogos & derivados , Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica/métodos , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Promielocítica Aguda/genética , 5-Metilcitosina/metabolismo , Animais , Células Cultivadas , Biologia Computacional , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Biblioteca Gênica , Estudo de Associação Genômica Ampla , Leucemia Promielocítica Aguda/metabolismo , Camundongos , Mutação , Nanotecnologia , Proteínas Proto-Oncogênicas/genética , Fatores de Tempo , Tirosina Quinase 3 Semelhante a fms/genética
Trends Immunol ; 37(2): 141-153, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26778079


Accumulating evidence indicates that the efficacy of tumor-targeted therapies relies on the host immune response, including targeted small-molecule and antibody approaches that were not previously thought to have an immune component. Here, we review the current understanding of how targeted therapies on tumor cells could have a major impact on the immune response, and how this relates to the therapeutic efficacy of these approaches. In this context, we evaluate different strategies that combine targeted therapies with immunotherapy approaches, and discuss past and ongoing clinical trials. We highlight gaps in knowledge, and argue that significant progress for combined therapies will require a better understanding of the complex interactions between immune cells, the tumor, and the tumor microenvironment (TME) in different cancer settings.

Imunidade Adaptativa , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Neoplasias/imunologia , Linfócitos T Citotóxicos/transplante , Microambiente Tumoral
Nat Med ; 21(10): 1209-15, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26322579


Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.

Antígeno CD47/imunologia , Imunoterapia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antineoplásicos/uso terapêutico , DNA/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto