KEGG   PATHWAY: hsa05235
Entry
hsa05235                    Pathway                                

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: overview
Pathway map
hsa05235  PD-L1 expression and PD-1 checkpoint pathway in cancer
hsa05235

Drug
D10316  Nivolumab (USAN/INN)
D10390  Pidilizumab (USAN)
D10574  Pembrolizumab (USAN)
D10773  Atezolizumab (USAN/INN)
D10808  Durvalumab (USAN/INN)
D10817  Avelumab (USAN)
D11108  Cemiplimab (USAN)
D11366  Dostarlimab (USAN)
D11487  Tislelizumab (USAN/INN)
D11488  Cetrelimab (USAN/INN)
D11532  Lodapolimab (USAN)
D11605  Spartalizumab (USAN/INN)
D11820  Balstilimab (USAN/INN)
D11827  Retifanlimab (USAN)
D11893  Bintrafusp alfa (INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3091  HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268]
1950  EGF; epidermal growth factor [KO:K04357]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
27436  EML4; EMAP like 4 [KO:K15420]
238  ALK; ALK receptor tyrosine kinase [KO:K05119] [EC:2.7.10.1]
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]
5728  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4793  NFKBIB; NFKB inhibitor beta [KO:K02581]
4794  NFKBIE; NFKB inhibitor epsilon [KO:K05872]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
3458  IFNG; interferon gamma [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 [KO:K05133]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
7097  TLR2; toll like receptor 2 [KO:K10159]
7099  TLR4; toll like receptor 4 [KO:K10160]
54106  TLR9; toll like receptor 9 [KO:K10161]
114609  TIRAP; TIR domain containing adaptor protein [KO:K05403]
4615  MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729]
7189  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:2.3.2.27]
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; toll like receptor adaptor molecule 1 [KO:K05842]
353376  TICAM2; toll like receptor adaptor molecule 2 [KO:K05409]
29126  CD274; CD274 molecule [KO:K06745]
5133  PDCD1; programmed cell death 1 [KO:K06744]
5777  PTPN6; protein tyrosine phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
5781  PTPN11; protein tyrosine phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
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]
1457  CSNK2A1; casein kinase 2 alpha 1 [KO:K03097] [EC:2.7.11.1]
1459  CSNK2A2; casein kinase 2 alpha 2 [KO:K03097] [EC:2.7.11.1]
283106  CSNK2A3; casein kinase 2 alpha 3 [KO:K03097] [EC:2.7.11.1]
1460  CSNK2B; casein kinase 2 beta [KO:K03115]
920  CD4; CD4 molecule [KO:K06454]
3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
916  CD3E; CD3e molecule [KO:K06451]
917  CD3G; CD3g molecule [KO:K06452]
919  CD247; CD247 molecule [KO:K06453]
915  CD3D; CD3d molecule [KO:K06450]
7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
4215  MAP3K3; mitogen-activated protein kinase kinase kinase 3 [KO:K04421] [EC:2.7.11.25]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
27040  LAT; linker for activation of T cells [KO:K07362]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
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]
940  CD28; CD28 molecule [KO:K06470]
5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
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
J Clin Pathol 71:189-194 (2018)
DOI:10.1136/jclinpath-2017-204853
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
Urol Oncol 35:14-20 (2017)
DOI:10.1016/j.urolonc.2016.10.004
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
Front Pharmacol 9:536 (2018)
DOI:10.3389/fphar.2018.00536
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
Mol Cancer 18:10 (2019)
DOI:10.1186/s12943-018-0928-4
Reference
  Authors
Bardhan K, Anagnostou T, Boussiotis VA
  Title
The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation.
  Journal
Front Immunol 7:550 (2016)
DOI:10.3389/fimmu.2016.00550
Reference
  Authors
Shi Y
  Title
Regulatory mechanisms of PD-L1 expression in cancer cells.
  Journal
Cancer Immunol Immunother 67:1481-1489 (2018)
DOI:10.1007/s00262-018-2226-9
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
Oncogene 37:4639-4661 (2018)
DOI:10.1038/s41388-018-0303-3
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
Ann Oncol 27:409-16 (2016)
DOI:10.1093/annonc/mdv615
Reference
  Authors
Glodde N, Holzel M
  Title
RAS and PD-L1: A Masters' Liaison in Cancer Immune Evasion.
  Journal
Immunity 47:1007-1009 (2017)
DOI:10.1016/j.immuni.2017.12.001
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
Oral Oncol 51:221-8 (2015)
DOI:10.1016/j.oraloncology.2014.11.014
Reference
  Authors
Nirschl CJ, Drake CG
  Title
Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy.
  Journal
Clin Cancer Res 19:4917-24 (2013)
DOI:10.1158/1078-0432.CCR-12-1972
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
Front Immunol 9:2569 (2018)
DOI:10.3389/fimmu.2018.02569
Reference
  Authors
Sharpe AH, Pauken KE
  Title
The diverse functions of the PD1 inhibitory pathway.
  Journal
Nat Rev Immunol 18:153-167 (2018)
DOI:10.1038/nri.2017.108
Reference
  Authors
Boussiotis VA
  Title
Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway.
  Journal
N Engl J Med 375:1767-1778 (2016)
DOI:10.1056/NEJMra1514296
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
Oncotarget 8:51936-51945 (2017)
DOI:10.18632/oncotarget.17232
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
Ann Transl Med 5:385 (2017)
DOI:10.21037/atm.2017.06.11
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
Mol Cell Biol 33:3091-8 (2013)
DOI:10.1128/MCB.00319-13
Reference
  Authors
Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X
  Title
New immunotherapies targeting the PD-1 pathway.
  Journal
Trends Pharmacol Sci 36:587-95 (2015)
DOI:10.1016/j.tips.2015.06.005
Reference
  Authors
Ok CY, Young KH
  Title
Targeting the programmed death-1 pathway in lymphoid neoplasms.
  Journal
Cancer Treat Rev 54:99-109 (2017)
DOI:10.1016/j.ctrv.2017.01.009
Related
pathway
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04066  HIF-1 signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04514  Cell adhesion molecules
hsa04620  Toll-like receptor signaling pathway
hsa04660  T cell receptor signaling pathway
KO pathway
ko05235   
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