RESUMO
Strategies that interfere with the binding of the receptor programmed cell death protein-1 (PD-1) to programmed death ligand-1 (PD-L1) have shown marked efficacy against many advanced cancers, including those that are negative for PD-L1. Precisely why patients with PD-L1 negative tumors respond to PD-1/PD-L1 checkpoint inhibition remains unclear. Here, we show that platelet-derived PD-L1 regulates the growth of PD-L1 negative tumors and that interference with platelet binding to PD-L1 negative cancer cells promotes T cell-induced cancer cytotoxicity. These results suggest that the successful outcomes of PD-L1 based therapies in patients with PD-L1 negative tumors may be explained, in part, by the presence of intra-tumoral platelets. Altogether, our findings demonstrate the impact of non-cancer/non-immune cell sources of PD-L1 in the tumor microenvironment in the promotion of cancer cell immune evasion. Our study also provides a compelling rationale for future testing of PD-L1 checkpoint inhibitor therapies in combination with antiplatelet agents, in patients with PD-L1 negative tumors.
Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Plaquetas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Sistema Imunitário , Imuno-Histoquímica , Células Jurkat , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Ativação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Estudos Retrospectivos , Linfócitos T/citologia , Microambiente TumoralRESUMO
Signal transducers and activators of transcription (STATs) are a group of proteins involved in signal transduction from numerous bioactive substances. Hormones and cytokines such as leukaemia inhibitory factor, interferon-tau and prolactin, which play key roles during early pregnancy, activate the Janus kinase (JAK)/STAT signalling pathway. The STATs are thus involved in the regulation of implantation, establishing uterine receptivity and regulation of the maternal immune response. It seems that STATs can orchestrate signals from hormones and cytokines in different cell types and may therefore generate numerous biological effects, despite the relatively small number of receptors activating the JAK/STAT pathway. This review summarizes the participation of STATs in the main processes of early pregnancy, especially regarding their pleiotropy and redundancy.
Assuntos
Janus Quinases/fisiologia , Prenhez/fisiologia , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais/fisiologia , Animais , Feminino , GravidezRESUMO
The implementation of a 10-channel parallel optical interconnect consisting of a two-dimensional array of vertical-cavity surface-emitting lasers, a 1.35-m fiber image guide, and a metal-semiconductor-metal receiver array is described. Transmission rates of 250 Mbits/s per channel are demonstrated with an optical cross talk of less than -27 dB and a loss of -3 dB. Coupling issues associated with image guides are analyzed and discussed.