内容紹介
Summary
Immune checkpoint blockade inhibition is a therapy which interferes with inhibitory signals placed upon immune cells, thereby eliciting anti-tumor responses. Although programmed death-1(PD-1)blockade therapy has been shown to be highly effective in clinical use, certain population of patients still fail to respond. Therefore, it is critical to determine how therapeutic efficacy of checkpoint inhibition can be enhanced. Recently, it has been shown that intracellular metabolism plays an important role in T cell differentiation and function. Because an effective tumor response relies on the differentiation of tumor-responsive effector cytotoxic T lymphocytes(CTLs), understanding such mechanisms will be essential for developing an improved therapeutic approach. Experiments on tumor-bearing mice have displayed strong anti-tumor responses upon combination therapy of PD-1 blockade and enhanced mitochondrial metabolism, through increased production of reactive oxygen species(ROS); upregulation of mechanistic target of rapamycin(mTOR)and AMP-activated protein kinase(AMPK); and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). In addition, the use of bezafibrate, a peroxisome proliferator-activated receptor(PPAR)agonist, in combination with PD-1 blockade resulted in improved effector function in CTLs. In this review, we will explore the mechanism behind T cell metabolism under the context of checkpoint blockade therapy, as well as how modulating T cell metabolism yields synergistic anti-tumor effects in combination with PD-1 blockade therapy.
要旨
免疫チェックポイント阻害療法は,免疫細胞の抑制状態を解除することにより免疫監視機構を再活性化させ,がん細胞への攻撃を再び可能にする治療法である。なかでもprogrammed death-1(PD-1)阻害抗体療法は高い臨床効果を示しているが不応答性の患者も存在するため,いかにして効果を向上させるかが今後の課題となる。近年では,細胞内代謝がT細胞の分化や機能制御において重要な役割を担っていることが明らかになってきた。本稿では,T細胞代謝の改善がPD-1阻害抗体療法を増強させる効果およびその作用機序について概説する。
目次
Immune checkpoint blockade inhibition is a therapy which interferes with inhibitory signals placed upon immune cells, thereby eliciting anti-tumor responses. Although programmed death-1(PD-1)blockade therapy has been shown to be highly effective in clinical use, certain population of patients still fail to respond. Therefore, it is critical to determine how therapeutic efficacy of checkpoint inhibition can be enhanced. Recently, it has been shown that intracellular metabolism plays an important role in T cell differentiation and function. Because an effective tumor response relies on the differentiation of tumor-responsive effector cytotoxic T lymphocytes(CTLs), understanding such mechanisms will be essential for developing an improved therapeutic approach. Experiments on tumor-bearing mice have displayed strong anti-tumor responses upon combination therapy of PD-1 blockade and enhanced mitochondrial metabolism, through increased production of reactive oxygen species(ROS); upregulation of mechanistic target of rapamycin(mTOR)and AMP-activated protein kinase(AMPK); and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). In addition, the use of bezafibrate, a peroxisome proliferator-activated receptor(PPAR)agonist, in combination with PD-1 blockade resulted in improved effector function in CTLs. In this review, we will explore the mechanism behind T cell metabolism under the context of checkpoint blockade therapy, as well as how modulating T cell metabolism yields synergistic anti-tumor effects in combination with PD-1 blockade therapy.
要旨
免疫チェックポイント阻害療法は,免疫細胞の抑制状態を解除することにより免疫監視機構を再活性化させ,がん細胞への攻撃を再び可能にする治療法である。なかでもprogrammed death-1(PD-1)阻害抗体療法は高い臨床効果を示しているが不応答性の患者も存在するため,いかにして効果を向上させるかが今後の課題となる。近年では,細胞内代謝がT細胞の分化や機能制御において重要な役割を担っていることが明らかになってきた。本稿では,T細胞代謝の改善がPD-1阻害抗体療法を増強させる効果およびその作用機序について概説する。