Regulation and Function of the PD-L1 Checkpoint

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2018 Mar 22

PMID 29562194

Citations 1041

Authors

Chong Sun

Riccardo Mezzadra

Ton N Schumacher

Affiliations

Soon will be listed here.

Abstract

Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies.

Citing Articles

Structural investigation of an RNA device that regulates PD-1 expression in mammalian cells.

Stagno J, Deme J, Dwivedi V, Lee Y, Lee H, Yu P Nucleic Acids Res. 2025; 53(5).

PMID: 40071935 PMC: 11897892. DOI: 10.1093/nar/gkaf156.

Co-delivery of axitinib and PD-L1 siRNA for the synergism of vascular normalization and immune checkpoint inhibition to boost anticancer immunity.

Liu Y, Gong L, Feng J, Xiao C, Liu C, Chen B J Nanobiotechnology. 2025; 23(1):194.

PMID: 40059141 PMC: 11892300. DOI: 10.1186/s12951-025-03170-y.

PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma.

Ding C, Yan F, Xu B, Qian H, Hong X, Liu S Cell Death Dis. 2025; 16(1):158.

PMID: 40050608 PMC: 11885674. DOI: 10.1038/s41419-025-07482-7.

A disproportionality analysis of real-world events from the FDA Adverse Event Reporting System (FAERS) for Atezolizumab.

Li Z, Zhu N, Liu Y, Yu Y, Wang T, Zou C BMC Pharmacol Toxicol. 2025; 26(1):51.

PMID: 40038564 PMC: 11881481. DOI: 10.1186/s40360-025-00879-2.

NSUN2/ALYREF axis-driven mC methylation enhances PD-L1 expression and facilitates immune evasion in non-small-cell lung cancer.

Yang Y, Cao L, Xu X, Li D, Deng Y, Li L Cancer Immunol Immunother. 2025; 74(4):132.

PMID: 40029463 PMC: 11876480. DOI: 10.1007/s00262-025-03986-5.

References

Green M, Rodig S, Juszczynski P, Ouyang J, Sinha P, ODonnell E . Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012; 18(6):1611-8. PMC: 3321508. DOI: 10.1158/1078-0432.CCR-11-1942. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Yamamoto H, Yamashita K, Perucho M . Somatic mutation of the beta2-microglobulin gene associates with unfavorable prognosis in gastrointestinal cancer of the microsatellite mutator phenotype. Gastroenterology. 2001; 120(6):1565-7. DOI: 10.1053/gast.2001.24497. View

Marzec M, Zhang Q, Goradia A, Raghunath P, Liu X, Paessler M . Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008; 105(52):20852-7. PMC: 2634900. DOI: 10.1073/pnas.0810958105. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A . Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291(5502):319-22. DOI: 10.1126/science.291.5502.319. View

Sumimoto H, Takano A, Teramoto K, Daigo Y . RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers. PLoS One. 2016; 11(11):e0166626. PMC: 5112979. DOI: 10.1371/journal.pone.0166626. View

Chang C, Qiu J, OSullivan D, Buck M, Noguchi T, Curtis J . Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015; 162(6):1229-41. PMC: 4864363. DOI: 10.1016/j.cell.2015.08.016. View

Dorand R, Nthale J, Myers J, Barkauskas D, Avril S, Chirieleison S . Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science. 2016; 353(6297):399-403. PMC: 5051664. DOI: 10.1126/science.aae0477. View

10.

Liu L, Mayes P, Eastman S, Shi H, Yadavilli S, Zhang T . The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015; 21(7):1639-51. DOI: 10.1158/1078-0432.CCR-14-2339. View

11.

Antonia S, Villegas A, Daniel D, Vicente D, Murakami S, Hui R . Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377(20):1919-1929. DOI: 10.1056/NEJMoa1709937. View

12.

Gros A, Parkhurst M, Tran E, Pasetto A, Robbins P, Ilyas S . Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016; 22(4):433-8. PMC: 7446107. DOI: 10.1038/nm.4051. View

13.

Ferris R, Blumenschein Jr G, Fayette J, Guigay J, Colevas A, Licitra L . Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016; 375(19):1856-1867. PMC: 5564292. DOI: 10.1056/NEJMoa1602252. View

14.

Ugi S, Maegawa H, Olefsky J, Shigeta Y, Kashiwagi A . Src homology 2 domains of protein tyrosine phosphatase are associated in vitro with both the insulin receptor and insulin receptor substrate-1 via different phosphotyrosine motifs. FEBS Lett. 1994; 340(3):216-20. DOI: 10.1016/0014-5793(94)80141-x. View

15.

Wang J, Jia Y, Zhao S, Zhang X, Wang X, Han X . BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer. Oncogene. 2017; 36(45):6235-6243. DOI: 10.1038/onc.2017.217. View

16.

Barber D, Wherry E, Masopust D, Zhu B, Allison J, Sharpe A . Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2005; 439(7077):682-7. DOI: 10.1038/nature04444. View

17.

Motzer R, Escudier B, Mcdermott D, George S, Hammers H, Srinivas S . Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373(19):1803-13. PMC: 5719487. DOI: 10.1056/NEJMoa1510665. View

18.

Twa D, Chan F, Ben-Neriah S, Woolcock B, Mottok A, Tan K . Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014; 123(13):2062-5. DOI: 10.1182/blood-2013-10-535443. View

19.

Thommen D, Schumacher T . T Cell Dysfunction in Cancer. Cancer Cell. 2018; 33(4):547-562. PMC: 7116508. DOI: 10.1016/j.ccell.2018.03.012. View

20.

Lastwika K, Wilson 3rd W, Li Q, Norris J, Xu H, Ghazarian S . Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2015; 76(2):227-38. DOI: 10.1158/0008-5472.CAN-14-3362. View