内容紹介
Regulation of T-cell Immune Exhaustion and Cancer Immunotherapy
Summary
In chronic infectious diseases and cancer, CD8+ T cells specific for viral and/or tumor antigens undergo repeated T cell receptor(TCR)stimulation due to the persistence of pathogens or cancer cells, gradually losing their ability to secrete interleukin 2(IL-2), tumor necrosis factor-α(TNF-α), and interferon-γ(IFN-γ). These CD8+ T cells are finally eliminated by apoptosis, a process referred to as immune exhaustion. The worsening immune function is accompanied by phenotypic changes in CD8+ T cells, for example, by changes in the expression of exhaustion markers such as programmed cell death protein 1(PD-1), cytotoxic T-lymphocyte antigen 4(CTLA-4), T cell immunoglobulin mucin 3(TIM-3), and lymphocyte activation gene 3(LAG-3). The exhaustion molecules on CD8+ T cells interact with their respective ligands and induce negative signals in activated T cells, leading to CD8+ T cell dysfunction. In 2013, the combined use of anti-PD-1 and anti-CTLA-4 antibodies was shown to induce extraordinary anti-tumor effects in patients with advanced melanoma. The regulation of exhausted CD8+ T cells has now emerged as a promising therapy to treat cancer.
要旨
感染症やがんでは,CD8 T細胞は繰り返す抗原刺激により疲弊(exhaustion)する。疲弊の過程で抗原特異的なCD8 T細胞はしだいにサイトカイン産生能を消失し,最終的にはアポトーシスにより死滅する。また,CD8 T細胞は持続的な抗原刺激により,疲弊分子PD-1,CTLA-4,TIM-3,LAG-3を発現する。これら疲弊分子とそのリガンドとの結合により発生する負のシグナルによりCD8 T細胞はより機能を消失する。2013年,抗PD-1,抗CTLA-4抗体により悪性黒色腫患者で劇的な腫瘍縮小効果が報告された。このようなCD8 T細胞疲弊の制御は,今後のがん治療に新たな展開をもたらすと考えられる。
目次
Summary
In chronic infectious diseases and cancer, CD8+ T cells specific for viral and/or tumor antigens undergo repeated T cell receptor(TCR)stimulation due to the persistence of pathogens or cancer cells, gradually losing their ability to secrete interleukin 2(IL-2), tumor necrosis factor-α(TNF-α), and interferon-γ(IFN-γ). These CD8+ T cells are finally eliminated by apoptosis, a process referred to as immune exhaustion. The worsening immune function is accompanied by phenotypic changes in CD8+ T cells, for example, by changes in the expression of exhaustion markers such as programmed cell death protein 1(PD-1), cytotoxic T-lymphocyte antigen 4(CTLA-4), T cell immunoglobulin mucin 3(TIM-3), and lymphocyte activation gene 3(LAG-3). The exhaustion molecules on CD8+ T cells interact with their respective ligands and induce negative signals in activated T cells, leading to CD8+ T cell dysfunction. In 2013, the combined use of anti-PD-1 and anti-CTLA-4 antibodies was shown to induce extraordinary anti-tumor effects in patients with advanced melanoma. The regulation of exhausted CD8+ T cells has now emerged as a promising therapy to treat cancer.
要旨
感染症やがんでは,CD8 T細胞は繰り返す抗原刺激により疲弊(exhaustion)する。疲弊の過程で抗原特異的なCD8 T細胞はしだいにサイトカイン産生能を消失し,最終的にはアポトーシスにより死滅する。また,CD8 T細胞は持続的な抗原刺激により,疲弊分子PD-1,CTLA-4,TIM-3,LAG-3を発現する。これら疲弊分子とそのリガンドとの結合により発生する負のシグナルによりCD8 T細胞はより機能を消失する。2013年,抗PD-1,抗CTLA-4抗体により悪性黒色腫患者で劇的な腫瘍縮小効果が報告された。このようなCD8 T細胞疲弊の制御は,今後のがん治療に新たな展開をもたらすと考えられる。