RESUMO
Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cetuximab/farmacologia , Células Dendríticas/efeitos dos fármacos , Interleucina-10/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacocinética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Comunicação Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab/farmacocinética , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Interleucina-10/farmacocinética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Programmed cell death ligand-1 (PD-L1) with its receptor PD-1 pathway is overactivated in many tumors. Inhibiting the interaction of PD-L1 and PD-1 is an attractive strategy to restore tumor-specific T cell immunity for tumor therapy. METHODS: A fully human anti-PD-L1 monoclonal antibody (mAb) B60-55 was identified by yeast surface display. The affinity, specificity, activity, and efficacy of mAb B60-55 were investigated in vitro or in vivo. RESULTS: mAb B60-55 (purity >99%) could bind to PD-L1 that is expressed on HEK293 cells with a dissociation constant of 0.2 nM, and specifically bind to human or cynomolgus macaque PD-L1 without a cross-reaction with murine PD-L1. Moreover, mAb B60-55 is an antagonistic antibody, which can block PD-L1 binding to its receptors, including PD-1 (PDCD1) and B7.1 (CD80). In vitro assays demonstrated the ability of mAb B60-55 to enhance T cell responses and cytokine production in the mixed lymphocyte reaction. In vivo studies showed that administration of mAb B60-55 exhibited a potent antitumor activity toward tumor cell carcinoma xenograft, with a mean half-life of 177.9h in cynomolgus monkeys. CONCLUSION: mAb B60-55 is a potential candidate for clinical development in cancer treatment.
Assuntos
Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais/imunologia , Antineoplásicos/imunologia , Antígeno B7-H1/imunologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Bloqueadores/isolamento & purificação , Anticorpos Monoclonais/isolamento & purificação , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Reações Cruzadas , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Teste de Cultura Mista de Linfócitos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
MicroRNAs/metabolismo , Atividade Motora/genética , Sistema Nervoso Periférico , Actinas/metabolismo , Fatores Etários , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Embrião não Mamífero , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , MicroRNAs/genética , Junção Neuromuscular/embriologia , Junção Neuromuscular/crescimento & desenvolvimento , Junção Neuromuscular/metabolismo , Sistema Nervoso Periférico/embriologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Sistema Nervoso Periférico/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Chromosomal rearrangement (CR) events result from abnormal breaking and rejoining of the DNA molecules, or from crossing-over between repetitive DNA sequences, and they are involved in many tumor and non-tumor diseases. Investigations of disease-associated CR events can not only lead to important discoveries about DNA breakage and repair mechanisms, but also offer important clues about the pathologic causes and the diagnostic/therapeutic targets of these diseases. We have developed a database of Chromosomal Rearrangements In Diseases (dbCRID, http://dbCRID.biolead.org), a comprehensive database of human CR events and their associated diseases. For each reported CR event, dbCRID documents the type of the event, the disease or symptoms associated, and--when possible--detailed information about the CR event including precise breakpoint positions, junction sequences, genes and gene regions disrupted and experimental techniques applied to discover/analyze the CR event. With 2643 records of disease-associated CR events curated from 1172 original studies, dbCRID is a comprehensive and dynamic resource useful for studying DNA breakage and repair mechanisms, and for analyzing the genetic basis of human tumor and non-tumor diseases.
Assuntos
Aberrações Cromossômicas , Bases de Dados Factuais , Doença/genética , Pontos de Quebra do Cromossomo , Humanos , Neoplasias/genética , Interface Usuário-ComputadorRESUMO
MicroRNAs (miRNAs) are a kind of endogenous non-coding small RNAs whose specific functions in animals are generally important. Although functions of some miRNAs have been identified, the role of miR-184 remains unknown. Here, we determined the temporal and spatial expression pattern of miR-184 during the different development stages and tissues in Drosophila. Strikingly, miR-184 is expressed ubiquitously in Drosophila embryos, larvae and adults, its expression pattern shows a dynamic changes during the development of embryo, especially in the central nervous system. This expression profile suggests that miR-184 may act important function in Drosophila development.