KEGG   PATHWAY: fca05235
fca05235                    Pathway                                
PD-L1 expression and PD-1 checkpoint pathway in cancer - Felis catus (domestic cat)
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.
Human Diseases; Cancer: overview
Pathway map
fca05235  PD-L1 expression and PD-1 checkpoint pathway in cancer

Felis catus (domestic cat) [GN:fca]
101083686  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
493978  EGF; pro-epidermal growth factor precursor [KO:K04357]
100510799  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:]
751103  HRAS; GTPase HRas isoform X1 [KO:K02833]
751104  KRAS; GTPase KRas [KO:K07827]
751105  NRAS; GTPase NRas [KO:K07828]
101096047  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:]
101081387  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:]
101100281  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
101087614  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
101087958  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
493935  FOS; proto-oncogene c-Fos [KO:K04379]
101097261  JUN; transcription factor AP-1 [KO:K04448]
101094586  EML4; echinoderm microtubule-associated protein-like 4 isoform X1 [KO:K15420]
101091689  ALK; ALK tyrosine kinase receptor isoform X2 [KO:K05119] [EC:]
100271864  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
101093286  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101093586  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101094274  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
101091892  PIK3CB; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
101097413  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
101091813  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:]
101087931  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
101092818  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:]
100499544  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
101098152  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:]
101091812  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X3 [KO:K04688] [EC:]
101092561  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:]
101095617  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:]
100142682  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:]
101086544  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
101090622  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
101099259  NFKBIB; NF-kappa-B inhibitor beta isoform X1 [KO:K02581]
101096065  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
100142683  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101096604  RELA; transcription factor p65 [KO:K04735]
493965  IFNG; interferon gamma precursor [KO:K04687]
101086811  IFNGR1; interferon gamma receptor 1 [KO:K05132]
101092286  IFNGR2; interferon gamma receptor 2 isoform X1 [KO:K05133]
101084377  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:]
101088959  JAK2; tyrosine-protein kinase JAK2 isoform X2 [KO:K04447] [EC:]
101084561  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
101095698  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
493797  TLR2; toll-like receptor 2 [KO:K10159]
493698  TLR4; toll-like receptor 4 precursor [KO:K10160]
493839  TLR9; toll-like receptor 9 precursor [KO:K10161]
101088688  TIRAP; toll/interleukin-1 receptor domain-containing adapter protein isoform X1 [KO:K05403]
101087092  MYD88; myeloid differentiation primary response protein MyD88 [KO:K04729]
101099750  TRAF6; TNF receptor-associated factor 6 [KO:K03175] [EC:]
101101259  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X3 [KO:K04446]
101080520  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
101083728  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
101082884  TICAM1; TIR domain-containing adapter molecule 1 [KO:K05842]
101090324  TIR domain-containing adapter molecule 2 [KO:K05409]
100127110  CD274; programmed cell death 1 ligand 1 [KO:K06745]
100135770  PDCD1; programmed cell death protein 1 precursor [KO:K06744]
101087073  PTPN6; tyrosine-protein phosphatase non-receptor type 6 isoform X2 [KO:K05697] [EC:]
101085500  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:]
101097987  BATF; basic leucine zipper transcriptional factor ATF-like [KO:K09034]
101082971  BATF3; basic leucine zipper transcriptional factor ATF-like 3 isoform X3 [KO:K09034]
101095682  BATF2; basic leucine zipper transcriptional factor ATF-like 2 isoform X1 [KO:K09034]
101084186  CSNK2A1; casein kinase II subunit alpha [KO:K03097] [EC:]
101093065  CSNK2A2; casein kinase II subunit alpha' isoform X1 [KO:K03097] [EC:]
101087664  CSNK2B; casein kinase II subunit beta [KO:K03115]
493775  CD4; T-cell surface glycoprotein CD4 precursor [KO:K06454]
101098805  LCK; tyrosine-protein kinase Lck isoform X2 [KO:K05856] [EC:]
493936  CD3E; T-cell surface glycoprotein CD3 epsilon chain precursor [KO:K06451]
101089292  CD3G; T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
111559549  uncharacterized protein LOC111559549 [KO:K10785]
101080604  CD247; T-cell surface glycoprotein CD3 zeta chain isoform X1 [KO:K06453]
101083107  CD3D; T-cell surface glycoprotein CD3 delta chain isoform X1 [KO:K06450]
101097059  tyrosine-protein kinase ZAP-70 isoform X2 [KO:K07360] [EC:]
101083633  MAP3K3; mitogen-activated protein kinase kinase kinase 3 isoform X1 [KO:K04421] [EC:]
101082274  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:]
101089813  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:]
101101135  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:]
101091536  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:]
111556320  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
105260786  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:]
101093319  LAT; linker for activation of T-cells family member 1 isoform X1 [KO:K07362]
101092925  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:]
101097144  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348] [EC:]
101086926  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:]
101093097  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X2 [KO:K04348] [EC:]
101097765  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
101090344  PPP3R1; calcineurin subunit B type 1 isoform X2 [KO:K06268]
101093110  RASGRP1; RAS guanyl-releasing protein 1 isoform X1 [KO:K04350]
493802  CD28; T-cell-specific surface glycoprotein CD28 precursor [KO:K06470]
101100730  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:]
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ
J Clin Pathol 71:189-194 (2018)
Zhou TC, Sankin AI, Porcelli SA, Perlin DS, Schoenberg MP, Zang X
A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment.
Urol Oncol 35:14-20 (2017)
Wang Y, Wang H, Yao H, Li C, Fang JY, Xu J
Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion.
Front Pharmacol 9:536 (2018)
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
Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape.
Mol Cancer 18:10 (2019)
Bardhan K, Anagnostou T, Boussiotis VA
The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation.
Front Immunol 7:550 (2016)
Shi Y
Regulatory mechanisms of PD-L1 expression in cancer cells.
Cancer Immunol Immunother 67:1481-1489 (2018)
Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T
Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations.
Oncogene 37:4639-4661 (2018)
Chen J, Jiang CC, Jin L, Zhang XD
Regulation of PD-L1: a novel role of pro-survival signalling in cancer.
Ann Oncol 27:409-16 (2016)
Glodde N, Holzel M
RAS and PD-L1: A Masters' Liaison in Cancer Immune Evasion.
Immunity 47:1007-1009 (2017)
Ritprajak P, Azuma M
Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma.
Oral Oncol 51:221-8 (2015)
Nirschl CJ, Drake CG
Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy.
Clin Cancer Res 19:4917-24 (2013)
Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, Cheong HC, Yong YK, Larsson M, Shankar EM
T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses.
Front Immunol 9:2569 (2018)
Sharpe AH, Pauken KE
The diverse functions of the PD1 inhibitory pathway.
Nat Rev Immunol 18:153-167 (2018)
Boussiotis VA
Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway.
N Engl J Med 375:1767-1778 (2016)
Arasanz H, Gato-Canas M, Zuazo M, Ibanez-Vea M, Breckpot K, Kochan G, Escors D
PD1 signal transduction pathways in T cells.
Oncotarget 8:51936-51945 (2017)
Zuazo M, Gato-Canas M, Llorente N, Ibanez-Vea M, Arasanz H, Kochan G, Escors D
Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy.
Ann Transl Med 5:385 (2017)
Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA
PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2.
Mol Cell Biol 33:3091-8 (2013)
Chinai JM, Janakiram M, Chen F, Chen W, Kaplan M, Zang X
New immunotherapies targeting the PD-1 pathway.
Trends Pharmacol Sci 36:587-95 (2015)
Ok CY, Young KH
Targeting the programmed death-1 pathway in lymphoid neoplasms.
Cancer Treat Rev 54:99-109 (2017)
fca04010  MAPK signaling pathway
fca04020  Calcium signaling pathway
fca04066  HIF-1 signaling pathway
fca04151  PI3K-Akt signaling pathway
fca04514  Cell adhesion molecules
fca04620  Toll-like receptor signaling pathway
fca04660  T cell receptor signaling pathway
KO pathway

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