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Nature ; 560(7718): 382-386, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089911

RESUMO

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2-4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.


Assuntos
Antígeno B7-H1/imunologia , Exossomos/metabolismo , Tolerância Imunológica/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/sangue , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Interferon gama/sangue , Interferon gama/imunologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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