1、共抑制相關因子PD-1作用的主要機制背景免疫抑制機制腫瘤激活機制缺陷&前景背景免疫抑制機制腫瘤激活機制缺陷&前景背景T細胞活化的雙信號模型第一信號：特異性抗原識別第二信號：輔助信號共刺激 | 共抑制PD-1程序性死亡受體11992年發現小鼠凋亡的細胞中表達T細胞抗原受體、細胞因子誘導產生B細胞、單核細胞敲除自身免疫病人60%同源背景免疫抑制機制腫瘤激活機制缺陷&前景結構N段：免疫球蛋白易變區類似結構20個氨基酸的桿部跨膜區胞質尾部：有酪氨酸信號基序ITIM招募胞內的 SHP-2 ，磷酸化ITSMSHP1、SHP2的停泊位點改變時抑制作用消失結構ITIM、ITSMKelly-Ann Sheppa

2、rd , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 結構N段：免疫球蛋白易變區類似結構20個氨基酸的桿部跨膜區胞質尾部：有酪氨酸信

3、號基序ITIM招募胞內的 SHP-2 ，磷酸化ITSMSHP1、SHP2的停泊位點改變時抑制作用消失結構ITSMChemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. J Immunol 2004;173:945-54. /content/173/2/945.longSHP-1 and SHP-2 associate with ITSM of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell

4、activation. 通路1Kelly-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly

5、-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly-Ann Sheppard , Lori

6、 J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly-Ann Sheppard , Lori J. Fitz , Julie M.

7、Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Bio

8、l 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phatase activity while decreasing PTEN protein stability by inhibiting casein kiinase 2. 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Biol 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phata

9、se activity while decreasing PTEN protein stability by inhibiting casein kiinase 2. 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Biol 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phatase activity while decreasing PTEN protein stability by inhibiting casein k

10、iinase 2. 通路3Ras-MEK-ERKPatsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 2012;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 通路3Ras-MEK-ERKPatsoukis N, Brown J,

11、 Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 2012;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 通路3Ras-MEK-ERKKelly-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Lette

12、rs , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路3Ras-MEK-ERKPatsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 201

13、2;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 新陳代謝變化Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramm

14、ing by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.PD1減少葡萄糖運輸和利用抑制氨基酸的轉運和代謝誘發內源性脂肪分解氧化新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolys

15、is and fatty acid oxidation.新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat

16、 Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化脂肪酸Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming b

17、y inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化脂肪酸Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.背景免疫抑制機制腫瘤激活

18、機制缺陷前景機制-適應性免疫抵抗Taube, J. M. et al. J. Sci Transl Med. 4, 127ra37 (2012). /content/4/127/127ra37.longColocalization of in ammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. 常用藥物Joel Sunshine, Janis M Taube Current Opinion in