RESUMO
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos/química , Antígenos/imunologia , Biomarcadores Tumorais , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunomodulação , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/mortalidade , Peptídeos/química , Peptídeos/imunologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
Nostocionone (Nost), a compound isolated from Nostoc commune, and its synthesized derivatives (NostDs) were evaluated for in vitro cytotoxicity against human T-cell leukemia Jurkat cells. NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-1,4-dien-3-one] inhibited cell growth more potently than Nost. To elucidate the mechanisms of NostD3-induced cell death, we examined changes in cell morphology, the loss of mitochondrial membrane potential (MMT), and DNA fragmentation. From these results, the cytotoxic effects of NostD3 were found to be mainly due to Type I programmed cell death (PCDI; i.e., apoptosis). Using caspase inhibitors, we further found that NostD-3-induced PCDI occurred through a caspase-independent pathway. Moreover, NostD3 decreased MMT and modulated multiple signaling molecules (MAPKs, Akt, Bcl-2, Bax, and c-Myc) in Jurkat cells, thereby inducing the release of endonuclease G (Endo-G) from mitochondria. The level of intracellular reactive oxygen species (ROS) in cells treated with NostD3 was elevated up to 1 h after the treatment. However, suppression of ROS by N-acetyl-l-cysteine restored Jurkat cell growth. Taken together, our data suggested that ROS production acted as a trigger in NostD3-induced PCDI in Jurkat cells through release of Endo-G from the mitochondria.
