Entry Name PD-L1 expression and PD-1 checkpoint pathway in cancer - Homo sapiens (human)
Description Programmed cell death 1 (PD1) and its ligand (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. In solid tumors, the PD-1/PD-L1 inhibitory pathway can be (mis-)used to silence the immune system by increasing the expression of PD-L1 on the tumor cell surface. Up-regulation of PD-L1 is caused by activation of pro-survival pathways MAPK and PI3K/Akt as well as transcriptional factors HIF-1, STAT3 and NF-kappa B. The MAPK and PI3K signalling pathways are activated by gene mutations and growth factors. PD-L1 on tumor cells may then engage the PD-1 receptors resulting in suppression of T-cell mediated immune response. Therapeutic antibodies blocking the PD-1/PD-L1 pathway by targeting PD-L1 or PD-1 are highly effective in rescuing T cell anti-tumor effector functions.
Class Human Diseases; Cancer: overviewBRITE hierarchy
Pathway map hsa05235 PD-L1 expression and PD-1 checkpoint pathway in cancer
Ortholog table Drug D10773 Atezolizumab (USAN/INN)
D11487 Tislelizumab (USAN/INN)
D11605 Spartalizumab (USAN/INN)
D11893 Bintrafusp alfa (USAN/INN)
D12764 Rilvegostomig (USAN/INN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 3091 HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
2353 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379 ]
3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
3459 IFNGR1; interferon gamma receptor 1 [KO:K05132 ]
3460 IFNGR2; interferon gamma receptor 2 [KO:K05133 ]
6772 STAT1; signal transducer and activator of transcription 1 [KO:K11220 ]
6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
114609 TIRAP; TIR domain containing adaptor protein [KO:K05403 ]
4615 MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729 ]
4772 NFATC1; nuclear factor of activated T cells 1 [KO:K04446 ]
4773 NFATC2; nuclear factor of activated T cells 2 [KO:K17332 ]
4775 NFATC3; nuclear factor of activated T cells 3 [KO:K17333 ]
148022 TICAM1; TIR domain containing adaptor molecule 1 [KO:K05842 ]
353376 TICAM2; TIR domain containing adaptor molecule 2 [KO:K05409 ]
55509 BATF3; basic leucine zipper ATF-like transcription factor 3 [KO:K09034 ]
10538 BATF; basic leucine zipper ATF-like transcription factor [KO:K09034 ]
116071 BATF2; basic leucine zipper ATF-like transcription factor 2 [KO:K09034 ]
916 CD3E; CD3 epsilon subunit of T-cell receptor complex [KO:K06451 ]
917 CD3G; CD3 gamma subunit of T-cell receptor complex [KO:K06452 ]
915 CD3D; CD3 delta subunit of T-cell receptor complex [KO:K06450 ]
7535 ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360 ] [EC:2.7.10.2 ]
27040 LAT; linker for activation of T cells [KO:K07362 ]
5534 PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268 ]
5535 PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268 ]
10125 RASGRP1; RAS guanyl releasing protein 1 [KO:K04350 ]
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ
Title PD-L1.
Journal Reference Authors Zhou TC, Sankin AI, Porcelli SA, Perlin DS, Schoenberg MP, Zang X
Title A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment.
Journal Reference Authors Wang Y, Wang H, Yao H, Li C, Fang JY, Xu J
Title Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion.
Journal Reference Authors Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, Wu X, Ma J, Zhou M, Li X, Li Y, Li G, Xiong W, Guo C, Zeng Z
Title Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape.
Journal Reference Authors Bardhan K, Anagnostou T, Boussiotis VA
Title The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation.
Journal Reference Authors Shi Y
Title Regulatory mechanisms of PD-L1 expression in cancer cells.
Journal Reference Authors Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T
Title Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations.
Journal Reference Authors Chen J, Jiang CC, Jin L, Zhang XD
Title Regulation of PD-L1: a novel role of pro-survival signalling in cancer.
Journal Reference Authors Glodde N, Holzel M
Title RAS and PD-L1: A Masters' Liaison in Cancer Immune Evasion.
Journal Reference Authors Ritprajak P, Azuma M
Title Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma.
Journal Reference Authors Nirschl CJ, Drake CG
Title Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy.
Journal Reference Authors Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, Cheong HC, Yong YK, Larsson M, Shankar EM
Title T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses.
Journal Reference Authors Sharpe AH, Pauken KE
Title The diverse functions of the PD1 inhibitory pathway.
Journal Reference Authors Boussiotis VA
Title Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway.
Journal Reference Authors Arasanz H, Gato-Canas M, Zuazo M, Ibanez-Vea M, Breckpot K, Kochan G, Escors D
Title PD1 signal transduction pathways in T cells.
Journal Reference Authors Zuazo M, Gato-Canas M, Llorente N, Ibanez-Vea M, Arasanz H, Kochan G, Escors D
Title Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy.
Journal Reference Authors Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA
Title PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2.
Journal Reference Authors Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X
Title New immunotherapies targeting the PD-1 pathway.
Journal Reference Authors Ok CY, Young KH
Title Targeting the programmed death-1 pathway in lymphoid neoplasms.
Journal Related hsa04620 Toll-like receptor signaling pathway
hsa04660 T cell receptor signaling pathway
KO pathway LinkDB All DBs
