PD-L1

from Wikipedia, the free encyclopedia
Programmed cell death 1 ligand 1
other names

PD-L1, B7 homolog 1, B7-H1

Existing structural data : PDB  3BIK , PDB  3BIS , PDB  3FN3

Properties of human protein
Mass / length primary structure 290 amino acids , 33,275 Da
Identifier
External IDs
Orthologue
human mouse
Entrez 29126 60533
Ensemble ENSG00000120217 ENSMUSG00000016496
UniProt Q9NZQ7 Q9EP73
Refseq (mRNA) NM_001267706.1 NM_021893
Refseq (protein) NP_001254635.1 NP_068693
Gene locus
PubMed search 29126 60533

Programmed cell death 1 ligand 1 (synonym CD274 , B7 homolog 1 ) is a surface protein and is involved in the inhibition of the immune response .

properties

PD-L1 is a type 1 transmembrane protein found in the cell membrane . It is produced in higher concentrations in the heart , skeletal muscles , placenta and lungs . In addition, it is produced in lower concentrations in the thymus , spleen , kidney , liver as well as activated T and B cells , dendritic cells , keratinocytes and monocytes . PD-L1 is glycosylated . It binds to the PD-1 receptor with a dissociation constant of 8 µM . Furthermore, PD-L1 binds to B7-1 (synonymous CD80 ) with a dissociation constant of 1.4 µM, but not to the closely related B7-2 (synonymous CD86 ).

regulation

The gene expression of PD-L1 is regulated by various mechanisms. After binding of IFN-γ to its receptor, the gene expression of PD-L1 in T cells, NK cells , macrophages , myeloid dendritic cells, B cells, and epithelial cells is increased. The promoter of PD-L1 binds the transcription factor IRF-1 (English interferon regulatory factor ). Resting cholangiocytes produce the PD-L1 mRNA , but not the protein, as the miRNA miR-513 inhibits them . Furthermore, miR-200, miR-197 and miRNA-34 are produced to inhibit the gene expression of PD-L1.

Immune modulation

Binding of PD-L1 to PD-1 inhibits the immune response by inducing gene expression of interleukin-10 in monocytes. It also inhibits the phosphorylation of ZAP70 and promotes gene expression of the ubiquitin ligase CBL-b .

PD-L1 is produced to a greater extent by some tumors during immune evasion . Inhibition of PD-L1 increases the pathogenicity of Listeria monocytogenes . Too little PD-L1 is produced in patients with lupus erythematosus . In persistent infections of LCMV and HIV , an increased gene expression of PD-1 is observed in CD8 -positive T cells (synonymous with cytotoxic T cells ). The increased activation of PD-1 by PD-L1 is believed to be involved in the anergy of cytotoxic T cells.

Applications

Immunostaining of PD-L1 in a lung tumor

A high concentration of PD-L1 in solid tumors is a negative prognostic marker, e.g. B. in melanoma , non-small cell lung cancer and in bladder cancer . The epigenetic methylation of the DNA of PD-L1 is a positive prognostic factor.

The concentration of PD-L1 is also examined prior to the use of antibodies against PD-1 in the context of cancer immunotherapy , whereby not all anti-PD1-sensitive tumors form PD-L1 and are therefore not recorded and in some cases, nevertheless, on cancer immunotherapy against PD- 1 address. The antibodies and immune checkpoint inhibitors nivolumab and pembrolizumab bind to PD-1, inhibit PD-1 activation by PD-L1 and are used for cancer immunotherapy. Antibodies that bind to PD-L1 are e.g. For example, BMS-936559, MPDL3280A ( Atezolizumab ) MEDI4736 ( Durvalumab ) and MSB0010718C ( Avelumab ) and REGN-2810 ( Cemiplimab ). The low molecular weight compound BMS-202 inhibits the binding of PD-L1 to PD-1 by forming PD-L1 homodimers .

Inhibition of PD-L1 is being investigated for the treatment of chronic infectious diseases such as tuberculosis and HIV .

PD-L1 diagnostics

Various scoring types are used for the therapy of PD-L1-positive tumors :

  • Tumor Proportion Score (TPS, percentage of PD-L1-positive tumor cells from all vital tumor cells)
  • Immune Cell Score (IC, percentage of the area of ​​PD-L1-positive immune cells from the area of ​​the vital tumor cells)
  • Combined Positive Score (CPS, combination of TIPS and IC), percentage of PD-L1-positive cells including lymphocytes and macrophages from all vital tumor cells

Web links

Individual evidence

  1. ↑ H. Dong, G. Zhu, K. Tamada, L. Chen: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. In: Nature medicine. Volume 5, Number 12, December 1999, pp. 1365-1369, doi : 10.1038 / 70932 , PMID 10581077 .
  2. ↑ Yoshiyuki Yamaguchi: Immunotherapy of Cancer. Springer, 2016, ISBN 978-4-431-55031-0 , p. 286.
  3. ^ MJ Butte, V. Peña-Cruz, MJ Kim, GJ Freeman, AH Sharpe: Interaction of human PD-L1 and B7-1. In: Molecular immunology. Volume 45, Number 13, August 2008, pp. 3567-3572, doi : 10.1016 / j.molimm.2008.05.014 , PMID 18585785 , PMC 3764616 (free full text).
  4. ↑ Flies DB, Chen L: The new B7s: playing a pivotal role in tumor immunity . In: Journal of Immunotherapy . 30, No. 3, April 2007, pp. 251-60. doi : 10.1097 / CJI.0b013e31802e085a . PMID 17414316 .
  5. ↑ Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH: Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma- induced upregulation of B7-H1 (CD274) . In: FEBS Letters . 580, No. 3, February 2006, pp. 755-62. doi : 10.1016 / j.febslet.2005.12.093 . PMID 16413538 .
  6. ↑ Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H: Expression of programmed death 1 ligands by murine T cells and APC . In: Journal of Immunology . 169, No. 10, November 2002, pp. 5538-45. doi : 10.4049 / jimmunol.169.10.5538 . PMID 12421930 .
  7. ^ Loke P, Allison JP: PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells . In: Proceedings of the National Academy of Sciences . 100, No. 9, April 2003, pp. 5336-41. doi : 10.1073 / pnas.0931259100 . PMID 12697896 . PMC 154346 (free full text).
  8. ↑ Gong AY, Zhou R, Hu G, Li X, Splinter PL, O'Hara SP, LaRusso NF, Soukup GA, Dong H, Chen XM: MicroRNA-513 regulates B7-H1 translation and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes . In: Journal of Immunology . 182, No. 3, February 2009, pp. 1325-33. doi : 10.4049 / jimmunol.182.3.1325 . PMID 19155478 . PMC 2652126 (free full text).
  9. ^ A. Grenda, P. Krawczyk: New Dancing Couple: PD-L1 and MicroRNA. In: Scandinavian journal of immunology. Volume 86, Number 3, September 2017, pp. 130-134, doi : 10.1111 / sji.12577 , PMID 28675453 .
  10. ^ EA Said, FP Dupuy, L. Trautmann, Y. Zhang, Y. Shi, M. El-Far, BJ Hill, A. Noto, P. Ancuta, Y. Peretz, SG Fonseca, J. Van Grevenynghe, MR Boulassel , J. Bruneau, NH Shoukry, JP Routy, DC Douek, EK Haddad, RP Sekaly: Programmed death-1-induced interleukin-10 production by monocytes impairs CD4 + T cell activation during HIV infection. In: Nature medicine. Volume 16, number 4, April 2010, pp. 452-459, doi : 10.1038 / nm.2106 , PMID 20208540 , PMC 4229134 (free full text).
  11. ^ KA Sheppard, LJ Fitz, JM Lee, C. Benander, JA George, J. Wooters, Y. Qiu, JM Jussif, LL Carter, CR Wood, D. Chaudhary: PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70 / CD3zeta signalosome and downstream signaling to PKCtheta. In: FEBS letters. Volume 574, number 1-3, September 2004, pp. 37-41, doi : 10.1016 / j.febslet.2004.07.083 , PMID 15358536 .
  12. ↑ K. Karwacz, C. Bricogne, D. MacDonald, F. Arce, CL Bennett, M. Collins, D. Escors: PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8 + T cells. In: EMBO molecular medicine. Volume 3, number 10, October 2011, pp. 581-592, doi : 10.1002 / emmm.201100165 , PMID 21739608 , PMC 3191120 (free full text).
  13. ↑ HO Alsaab, S. Sow, R. Alzhrani, K. Tatiparti, K. Bhise, SK Kashaw, AK Iyer: PD-1 and PD-L1 checkpoint signaling inhibition for Cancer Immunotherapy: Mechanism, combinations, and Clinical Outcome. In: Frontiers in pharmacology. Volume 8, 2017, p. 561, doi : 10.3389 / fphar.2017.00561 , PMID 28878676 , PMC 5572324 (free full text).
  14. ↑ Seo SK, Jeong HY, Park SG, Lee SW, Choi IW, Chen L, Choi I: Blockade of endogenous B7-H1 suppresses antibacterial protection after primary Listeria monocytogenes infection . In: Immunology . 123, No. 1, January 2008, pp. 90-9. doi : 10.1111 / j.1365-2567.2007.02708.x . PMID 17971153 . PMC 2433284 (free full text).
  15. ↑ Mozaffarian N, Wiedeman AE, Stevens AM: Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1 . In: Rheumatology . 47, No. 9, September 2008, pp. 1335-41. doi : 10.1093 / rheumatology / ken256 . PMID 18650228 . PMC 2722808 (free full text).
  16. ↑ a b Waun Ki Hong: Holland-Frei Cancer Medicine 8. PMPH-USA, 2010, ISBN 978-1-607-95014-1 , p. 185.
  17. ↑ P. Wu, D. Wu, L. Li, Y. Chai, J. Huang: PD-L1 and Survival in Solid Tumors: A Meta-Analysis. In: PloS one. Volume 10, number 6, 2015, p. E0131403, doi : 10.1371 / journal.pone.0131403 , PMID 26114883 , PMC 4483169 (free full text).
  18. ↑ Gevensleben H, Holmes EE, Goltz D, Dietrich J, Sailer V, Ellinger J, Dietrich D, Kristiansen G: PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy . In: Oncotarget . 7, No. 48, November 2016, pp. 79943-79955. doi : 10.18632 / oncotarget.13161 . PMID 27835597 . PMC 5346762 (free full text).
  19. ^ A. Ribas, S. Hu-Lieskovan: What does PD-L1 mean positive or negative? In: The Journal of experimental medicine. Volume 213, number 13, December 2016, pp. 2835–2840, doi : 10.1084 / jem.20161462 , PMID 27903604 , PMC 5154949 (free full text).
  20. ↑ Shuren Zhang: Progress in Cancer Immunotherapy. Springer, 2016, ISBN 978-9-401-77555-7 , p. 37.
  21. ↑ David Kerr: Immunotherapy for Gastrointestinal Cancer. Springer, 2017, ISBN 978-3-319-43063-8 , p. 129.
  22. ↑ MK Callahan, MA Postow, JD Wolchok: Targeting T Cell Co-receptors for Cancer Therapy. In: Immunity. Volume 44, number 5, May 2016, pp. 1069-1078, doi : 10.1016 / j.immuni.2016.04.023 , PMID 27192570 .
  23. ^ A. Ito, S. Kondo, K. Tada, S. Kitano: Clinical Development of Immune Checkpoint Inhibitors. In: BioMed research international. Volume 2015, 2015, p. 605478, doi : 10.1155 / 2015/605478 , PMID 26161407 , PMC 4486755 (free full text).
  24. ↑ K. Shih, HT Arkenau, JR Infante: Clinical impact of checkpoint inhibitors as novel cancer therapies. In: Drugs. Volume 74, number 17, November 2014, pp. 1993-2013, doi : 10.1007 / s40265-014-0305-6 , PMID 25344022 , PMC 4224737 (free full text).
  25. ↑ KM Zak, P. Grudnik, K. Magiera, A. Dömling, G. Dubin, TA Holak: Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1 / PD-L2. In: Structure. Volume 25, number 8, August 2017, pp. 1163–1174, doi : 10.1016 / j.str.2017.06.011 , PMID 28768162 .
  26. ^ M. Rao, D. Valentini, E. Dodoo, A. Zumla, M. Maeurer: Anti-PD-1 / PD-L1 therapy for infectious diseases: learning from the cancer paradigm. In: International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases. Volume 56, March 2017, pp. 221-228, doi : 10.1016 / j.ijid.2017.01.028 , PMID 28163164 .
  27. ↑ V. Velu, RD Shetty, M. Larsson, EM Shankar: Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. In: Retrovirology. Volume 12, February 2015, p. 14, doi : 10.1186 / s12977-015-0144-x , PMID 25756928 , PMC 4340294 (free full text).