切换至 "中华医学电子期刊资源库"

中华临床医师杂志(电子版) ›› 2020, Vol. 14 ›› Issue (02) : 149 -153. doi: 10.3877/cma.j.issn.1674-0785.2020.02.015

所属专题: 文献

综述

参与调控细胞程序性死亡蛋白1及其配体1信号通路的研究进展
贾玲玲1, 张文凯2,(), 刘凯1, 赵希伟1, 刘倩1, 侯林义1   
  1. 1. 030001 太原,山西医科大学第二医院心胸外科
    2. 030001 太原,山西医科大学第二医院重症医学科
  • 收稿日期:2019-08-28 出版日期:2020-02-15
  • 通信作者: 张文凯

Advances in research of regulation of PD-1/PD-L1 signaling pathway

Lingling Jia1, Wenkai Zhang2,(), Kai Liu1, Xiwei Zhao1, Qian Liu1, Linyi Hou1   

  1. 1. Department of Cardiothoracic Surgery, Second Hospital of Shanxi Medical University, Taiyuan 030001, China
    2. Intensive Care Unit, Second Hospital of Shanxi Medical University, Taiyuan 030001, China
  • Received:2019-08-28 Published:2020-02-15
  • Corresponding author: Wenkai Zhang
  • About author:
    Corresponding author: Zhang Wenkai, Email:
引用本文:

贾玲玲, 张文凯, 刘凯, 赵希伟, 刘倩, 侯林义. 参与调控细胞程序性死亡蛋白1及其配体1信号通路的研究进展[J/OL]. 中华临床医师杂志(电子版), 2020, 14(02): 149-153.

Lingling Jia, Wenkai Zhang, Kai Liu, Xiwei Zhao, Qian Liu, Linyi Hou. Advances in research of regulation of PD-1/PD-L1 signaling pathway[J/OL]. Chinese Journal of Clinicians(Electronic Edition), 2020, 14(02): 149-153.

细胞程序性死亡蛋白1及其配体1(PD-1/PD-L1)通路已经成为研究热点,无论在抗肿瘤还是在抗炎方面均取得了一定的成果,但具体的机制目前尚不完全清楚。本文介绍了PD-1及PD-L1的分子结构、功能以及与其他通路之间的关系。PD-1蛋白是免疫抑制分子,与其配体PD-L1结合起促进细胞凋亡的作用。在肿瘤或炎症中,JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路被激活,诱导免疫细胞及肿瘤细胞高表达PD-1及PD-L1,使免疫细胞活性降低,消耗增加,募集减少,从而使机体抗肿瘤、抗炎能力下降。PD-1/PD-L1与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路也起相互调控作用。PD-1/PD-L1抑制剂与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等通路抑制剂联合应用,在抗肿瘤以及肿瘤耐药性方面取得了突破性进展。然而,相对于PD-1/PD-L1对肿瘤作用的研究而言,PD-1/PD-L1在炎症方面的研究相对较少,无相应的药物应用于临床,需要大量的基础研究支持。

The programmed cell death protein 1 (PD-1) and programmed death receptor ligand-1 (PD-L1) pathway has become a hot research topic, and some results have been achieved both in anti-tumor and anti-inflammatory research. However, the specific mechanism is not completely clear. This article describes the molecular structure and function of PD-1 and PD-L1 and the relationship between PD-1 and PD-L1. PD-1 is an immunosuppressive molecule that binds to its ligand PD-L1 to promote apoptosis. In tumors or inflammation, other signaling pathways such as JAK/STAT, NF-κB, MAPK, PI3K, and TIM-3/Gal-9 are activated, inducing immune cells and tumor cells to overexpress PD-1 and PD-L1. As a result, immune cell activity is reduced, consumption is increased, and recruitment is reduced, which reduces the body’s ability to resist tumors and inflammation. PD-1/PD-L1 interacts with other signaling pathways such as JAK/STAT, NF-κB, MAPK, PI3K, and TIM-3/Gal-9, and PD-1/PD-L1 inhibitors can be used in combination with JAK/STAT, NF-κB, MAPK, PI3K, and TIM-3/Gal-9 pathway inhibitors; much progress has been achieved in anti-tumor therapy and tumor drug resistance. However, compared to the research on the effects of PD-1/PD-L1 on tumors, there is relatively little research on PD-1/PD-L1 in inflammation. There is no corresponding drug for clinical treatment, which requires much basic experimental research support.

[1]
Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death [J]. EMBO J, 1992, 11(11): 3887-3895.
[2]
Sharma P, Allison JP. The future of immune checkpoint therapy [J]. Science, 2015, 348(6230): 56-61.
[3]
Huang X, Venet F, Wang YL, et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis [J]. Proc Natl Acad Sci U S A, 2009, 106(15): 6303-6308.
[4]
Gupta A, Berg DT, Gerlitz B, et al. Role of protein C in renal dysfunction after polymicrobial sepsis [J]. J Am Soc Nephrol, 2007, 18(3): 860-867.
[5]
何义,林飞,潘灵辉, 等. 程序性细胞死亡因子-1在大鼠肺缺血再灌注损伤中的作用 [J]. 实用医学杂志, 2019, 35(8): 1216-1221.
[6]
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity [J]. Annu Rev Immunol, 2008, 26: 677-704.
[7]
Shinohara T, Taniwaki M, Ishida Y, et al. Structure and chromosomal localization of the human PD-1 gene (PDCD1) [J]. Genomics, 1994, 23(3): 704-706.
[8]
Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion [J]. Nat Med, 1999, 5(12): 1365-1369.
[9]
Latchman Y, Wood C R, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation [J]. Nat Immunol, 2001, 2(3): 261-268.
[10]
Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands and other features of the tumor immune microenvironment with response to anti-PD-1 therapy [J]. Clin Cancer Res, 2014, 20(19): 5064-5074.
[11]
Tabanelli V, Corsini C, Fiori S, et al. Recurrent PDL1 expression and PDL1 (CD274) copy number alterations in breast implant-associated anaplastic large cell lymphomas [J]. Hum Pathol, 2019, 90: 60-69.
[12]
Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8 T cell tumor-infiltration impairing anti-PD1 therapy [J]. Nat Commun, 2019, 10(1): 2416.
[13]
Giordano G, Parcesepe P, D'Andrea MR, et al. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer [J]. J Exp Clin Cancer Res, 2019, 38(1): 28.
[14]
Garcia Fortanet J, Chen CH, Chen YN, et al. Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor [J]. J Med Chem, 2016, 59(17): 7773-7782.
[15]
Li J, Jie HB, Lei Y, et al. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment [J]. Cancer Res, 2015, 75(3): 508-518.
[16]
Nakayama Y, Mimura K, Tamaki T, et al. Phospho-STAT1 expression as a potential biomarker for anti-PD-1/anti-PD-L1 immunotherapy for breast cancer [J]. Int J Oncol, 2019, 54(6): 2030-2038.
[17]
Tsukamoto M, Imai K, Ishimoto T, et al. PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis [J]. Cancer Sci, 2019, 110(1): 310-320.
[18]
Chen W, Wang J, Jia L, et al. Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan [J]. Cell Death Dis, 2016, 7(2): e2115.
[19]
Wang D, Li X, Li J, et al. APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression [J]. Gut, 2019, 68(10): 1846-1857.
[20]
Wang W, Chapman NM, Zhang B, et al. Upregulation of PD-L1 via HMGB1-activated IRF3 and NF-κB contributes to UV radiation-induced immune suppression [J]. Cancer Res, 2019, 79(11): 2909-2922.
[21]
Aguilera TA, Giaccia AJ. Molecular pathways: oncologic pathways and their role in T-cell exclusion and immune evasion-A new role for the AXL receptor tyrosine kinase [J]. Clin Cancer Res, 2017, 23(12): 2928-2933.
[22]
Bouillez A, Rajabi H, Jin C, et al. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer [J]. Oncogene, 2017, 36(28): 4037-4046.
[23]
Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma [J]. Oral Oncol, 2015, 51(3): 221-228.
[24]
Li W, Tu J, Liu X, et al. Farnesyltransferase inhibitor FTI-277 inhibits PD-L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation [J]. Clin Exp Immunol, 2017, 190(1): 8-18.
[25]
Loi S, Dushyanthen S, Beavis PA, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors [J]. Clin Cancer Res, 2016, 22(6): 1499-1509.
[26]
Gao M, Lin M, Moffitt RA, et al. Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer [J]. Br J Cancer, 2019, 120(1): 88-96.
[27]
Hugo W, Shi H, Sun L, et al. Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance [J]. Cell, 2015, 162(6): 1271-1285.
[28]
Lin HY, Chin YT, Nana AW, et al. Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells [J]. Steroids, 2016, 114: 59-67.
[29]
Jiang X, Zhou J, Giobbie-Hurder A, et al. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition [J]. Clin Cancer Res, 2013, 19(3): 598-609.
[30]
Zhang Y, Velez-Delgado A, Mathew E, et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer [J]. Gut, 2017, 66(1): 124-136.
[31]
Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors [J]. Cancer Discov, 2013, 3(12): 1355-1363.
[32]
Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer [J]. Cancer Immunol Res, 2014, 2(4): 361-370.
[33]
Kim YB, Ahn JM, Bae WJ, et al. Functional loss of ARID1A is tightly associated with high PD-L1 expression in gastric cancer [J]. Int J Cancer, 2019, 145(4): 916-926.
[34]
Wei F, Zhang T, Deng SC, et al. PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways [J]. Cancer Lett, 2019, 450: 1-13.
[35]
Zhao R, Song Y, Wang Y, et al. PD-1/PD-L1 blockade rescue exhausted CD8T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway [J]. Cell Prolif, 2019, 52(3): e12571.
[36]
Chen M, Sharma A, Lin Y, et al. Insluin and epithelial growth factor (EGF) promote programmed death ligand 1(PD-L1) production and transport in colon cancer stem cells [J]. BMC Cancer, 2019, 19(1): 153.
[37]
Fei Z, Deng Z, Zhou L, et al. PD-L1 induces epithelial-mesenchymal transition in nasopharyngeal carcinoma cells through activation of the PI3K/AKT pathway [J]. Oncol Res, 2019, 27(7): 801-807.
[38]
Atefi M, Avramis E, Lassen A, et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma [J]. Clin Cancer Res, 2014, 20(13): 3446-3457.
[39]
Dama P, Tang M, Fulton N, et al. Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy [J]. J Immunother Cancer, 2019, 7(1): 175.
[40]
Tyler PM, Servos MM, de Vries RC, et al. Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy [J]. Mol Cancer Ther, 2017, 16(3): 428-439.
[41]
Hays E, Bonavida B. YY1 regulates cancer cell immune resistance by modulating PD-L1 expression [J]. Drug Resist Updat, 2019, 43: 10-28.
[42]
Staples KJ, Nicholas B, McKendry RT, et al. Viral infection of human lung macrophages increases PDL1 expression via IFNβ [J]. PLoS One, 2015, 10(3): e0121527.
[1] 唐丹, 姚晓曦, 杨博文, 薛绍龙, 李梦瑶, 韦柳杏, 郄明蓉. 双肾上腺皮质激素样激酶1对子宫内膜样腺癌患者临床特征的影响[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(05): 582-590.
[2] 曾德荣, 马琳, 李星瀚, 胡伟涛, 刘琦, 邓永强. 多聚ADP核糖聚合酶1在口腔鳞状细胞癌精准诊疗中的作用机制及转化价值[J/OL]. 中华口腔医学研究杂志(电子版), 2024, 18(04): 269-275.
[3] 李星月, 董伟, 徐永波, 张文法, 胡晓璇, 钟玉绪, 褚海波. 浅表血栓性静脉炎管壁基质金属蛋白酶及其抑制剂表达研究[J/OL]. 中华普通外科学文献(电子版), 2024, 18(05): 338-343.
[4] 汤宏涛, 何坤. 中晚期肝细胞癌介入治疗的进展及前景[J/OL]. 中华普通外科学文献(电子版), 2024, 18(04): 305-308.
[5] 李智, 冯芸. NF-κB 与MAPK 信号通路及其潜在治疗靶点在急性呼吸窘迫综合征中的研究进展[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(05): 840-843.
[6] 郑琪, 马婕群, 张彦兵, 廖子君, 张锐. EPHA5突变预测肺腺癌免疫检查点抑制剂治疗预后的临床意义[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(04): 548-552.
[7] 胡志伟, 吴继敏, 邓昌荣, 战秀岚, 纪涛, 王峰, 田书瑞, 陈冬, 张玉, 刘健男, 宋庆. 抗反流黏膜套扎治疗顽固性胃食管反流病[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(04): 227-233.
[8] 张敏, 朱建华, 缪雅芳, 郭锦荣. 菝葜皂苷元对肝癌HepG2细胞抑制作用的机制研究[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(06): 328-335.
[9] 季加翠, 孙春斌, 罗恩丽. 姜黄素通过调节NF-κB/NLRP3通路减轻LPS诱导小胶质细胞神经炎症损伤[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(04): 193-203.
[10] 魏志鸿, 刘建勇, 吴小雅, 杨芳, 吕立志, 江艺, 蔡秋程. 肝移植术后急性移植物抗宿主病的诊治(附四例报告)[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 846-851.
[11] 陈伟杰, 何小东. 胆囊癌免疫靶向治疗进展[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 763-768.
[12] 施麟宵, 洪兰兰, 阳柳, 芶碧珍, 刘畅, 吴欣. 钠-葡萄糖协同转运蛋白2 抑制剂治疗原发性膜性肾病的疗效及其对Th1/Th2 的影响[J/OL]. 中华肾病研究电子杂志, 2024, 13(05): 261-267.
[13] 马豆豆, 丁艳, 古今, 王丽芳, 石连杰. 以发热为首发表现的强直性脊柱炎合并潜伏性结核感染一例[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 791-794.
[14] 徐靖亭, 孔璐. PARP抑制剂治疗卵巢癌的耐药机制及应对策略[J/OL]. 中华临床医师杂志(电子版), 2024, 18(06): 584-588.
[15] 靳英, 付小霞, 陈美茹, 袁璐, 郝力瑶. CD147调控MAPK信号通路对结肠癌细胞增殖和凋亡的影响及机制研究[J/OL]. 中华临床医师杂志(电子版), 2024, 18(05): 474-480.
阅读次数
全文


摘要