Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2021

Open Access 01-12-2021 | NSCLC | Review

Regulation of PD-L1 expression in the tumor microenvironment

Authors: Ming Yi, Mengke Niu, Linping Xu, Suxia Luo, Kongming Wu

Published in: Journal of Hematology & Oncology | Issue 1/2021

Login to get access

Abstract

Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.
Literature
1.
2.
3.
4.
5.
6.
7.
Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18:10.PubMedPubMedCentralCrossRef
8.
9.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.CrossRefPubMed
10.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.PubMedPubMedCentralCrossRef
11.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.CrossRefPubMed
12.
Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17:717–26.PubMedCrossRef
13.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.PubMedPubMedCentralCrossRef
14.
Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91.PubMedPubMedCentralCrossRef
15.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015–26.PubMedPubMedCentralCrossRef
16.
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.CrossRefPubMed
17.
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.PubMedPubMedCentralCrossRef
18.
Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the Phase II KEYNOTE-158 study. J Clin Oncol. 2019;37:1470–8.PubMedCrossRef
19.
Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12:54.PubMedPubMedCentralCrossRef
20.
21.
22.
23.
Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34:2690–7.PubMedPubMedCentralCrossRef
24.
George J, Saito M, Tsuta K, Iwakawa R, Shiraishi K, Scheel AH, et al. Genomic amplification of CD274 (PD-L1) in small-cell lung cancer. Clin Cancer Res. 2017;23:1220–6.PubMedCrossRef
25.
Twa DD, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A, Tan KL, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123:2062–5.PubMedCrossRef
26.
Howe FS, Fischl H, Murray SC, Mellor J. Is H3K4me3 instructive for transcription activation? BioEssays. 2017;39:1–12.PubMedCrossRef
27.
Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, et al. The MLL1-H3K4me3 axis-mediated pd-l1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst. 2017;109.
28.
29.
Xiao G, Jin LL, Liu CQ, Wang YC, Meng YM, Zhou ZG, et al. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma. J Immunother Cancer. 2019;7:300.PubMedPubMedCentralCrossRef
30.
Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR, et al. Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy. Trends Immunol. 2019;40:328–44.PubMedCrossRef
31.
Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5:587–98.PubMedPubMedCentralCrossRef
32.
Chatterjee A, Rodger EJ, Ahn A, Stockwell PA, Parry M, Motwani J, et al. Marked global DNA hypomethylation is associated with constitutive PD-L1 expression in melanoma. iScience. 2018;4:312–25.
33.
Micevic G, Thakral D, McGeary M, Bosenberg MW. PD-L1 methylation regulates PD-L1 expression and is associated with melanoma survival. Pigment Cell Melanoma Res. 2019;32:435–40.PubMedCrossRef
34.
Franzen A, Vogt TJ, Müller T, Dietrich J, Schröck A, Golletz C, et al. PD-L1 (CD274) and PD-L2 (PDCD1LG2) promoter methylation is associated with HPV infection and transcriptional repression in head and neck squamous cell carcinomas. Oncotarget. 2018;9:641–50.PubMedCrossRef
35.
Goltz D, Gevensleben H, Dietrich J, Dietrich D. PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients. Oncoimmunology. 2017;6:e1257454.PubMedCrossRef
36.
Asgarova A, Asgarov K, Godet Y, Peixoto P, Nadaradjane A, Boyer-Guittaut M, et al. PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma. Oncoimmunology. 2018;7:e1423170.PubMedPubMedCentralCrossRef
37.
Zhu T, Hu Z, Wang Z, Ding H, Li R, Sun J, et al. Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma. Int Immunopharmacol. 2020;82:106245.PubMedCrossRef
38.
Clayton AL, Hazzalin CA, Mahadevan LC. Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell. 2006;23:289–96.PubMedCrossRef
39.
Wang H, Fu C, Du J, Wang H, He R, Yin X, et al. Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells. J Exp Clin Cancer Res. 2020;39:29.PubMedPubMedCentralCrossRef
40.
Woods DM, Sodré AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 2015;3:1375–85.PubMedPubMedCentralCrossRef
41.
42.
Deng S, Hu Q, Zhang H, Yang F, Peng C, Huang C. HDAC3 inhibition upregulates PD-L1 expression in B-cell lymphomas and augments the efficacy of anti-PD-L1 therapy. Mol Cancer Ther. 2019;18:900–8.PubMedCrossRef
43.
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. 2018;37:4639–61.PubMedPubMedCentralCrossRef
44.
Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.PubMedPubMedCentralCrossRef
45.
Yao S, Jiang L, Moser EK, Jewett LB, Wright J, Du J, et al. Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection. Mucosal Immunol. 2015;8:746–59.PubMedCrossRef
46.
Moon JW, Kong SK, Kim BS, Kim HJ, Lim H, Noh K, et al. IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma. Sci Rep. 2017;7:17810.PubMedPubMedCentralCrossRef
47.
Blazanin N, Cheng T, Carbajal S, DiGiovanni J. Activation of a protumorigenic IFNγ/STAT1/IRF-1 signaling pathway in keratinocytes following exposure to solar ultraviolet light. Mol Carcinog. 2019;58:1656–69.PubMedCrossRef
48.
Yan Y, Zheng L, Du Q, Yan B, Geller DA. Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells. Cancer Immunol Immunother. 2020;69:1891–903.PubMedCrossRef
49.
Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188–201.PubMedCrossRef
50.
Xu L, Chen X, Shen M, Yang DR, Fang L, Weng G, et al. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol Oncol. 2018;12:269–86.PubMedPubMedCentralCrossRef
51.
Zhang W, Liu Y, Yan Z, Yang H, Sun W, Yao Y, et al. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer. 2020;8:e000285.PubMedPubMedCentralCrossRef
52.
Lamano JB, Lamano JB, Li YD, DiDomenico JD, Choy W, Veliceasa D, et al. Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. Clin Cancer Res. 2019;25:3643–57.PubMedPubMedCentralCrossRef
53.
Shen MJ, Xu LJ, Yang L, Tsai Y, Keng PC, Chen Y, et al. Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget. 2017;8:80506–20.PubMedPubMedCentralCrossRef
54.
Wang X, Yang L, Huang F, Zhang Q, Liu S, Ma L, et al. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett. 2017;184:7–14.PubMedPubMedCentralCrossRef
55.
Quandt D, Jasinski-Bergner S, Müller U, Schulze B, Seliger B. Synergistic effects of IL-4 and TNFα on the induction of B7–H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation. J Transl Med. 2014;12:151.PubMedPubMedCentralCrossRef
56.
Jiang C, Yuan F, Wang J, Wu L. Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages. Immunobiology. 2017;222:651–7.PubMedCrossRef
57.
Carbotti G, Barisione G, Airoldi I, Mezzanzanica D, Bagnoli M, Ferrero S, et al. IL-27 induces the expression of IDO and PD-L1 in human cancer cells. Oncotarget. 2015;6:43267–80.PubMedPubMedCentralCrossRef
58.
Starke A, Wüthrich RP, Waeckerle-Men Y. TGF-beta treatment modulates PD-L1 and CD40 expression in proximal renal tubular epithelial cells and enhances CD8 cytotoxic T-cell responses. Nephron Exp Nephrol. 2007;107:e22–9.PubMedCrossRef
59.
60.
David JM, Dominguez C, McCampbell KK, Gulley JL, Schlom J, Palena C. A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology. 2017;6:e1349589.PubMedPubMedCentralCrossRef
61.
Ni XY, Sui HX, Liu Y, Ke SZ, Wang YN, Gao FG. TGF-β of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep. 2012;28:615–21.PubMedCrossRef
62.
Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355–63.PubMedCrossRef
63.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585–93.PubMedPubMedCentralCrossRef
64.
Garassino MC, Gelibter AJ, Grossi F, Chiari R, Soto Parra H, Cascinu S, et al. Italian nivolumab expanded access program in nonsquamous non-small cell lung cancer patients: results in never-smokers and EGFR-mutant patients. J Thorac Oncol. 2018;13:1146–55.PubMedCrossRef
65.
Garassino MC, Cho BC, Kim JH, Mazières J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018;19:521–36.PubMedPubMedCentralCrossRef
66.
67.
Stutvoet TS, Kol A, de Vries EG, de Bruyn M, Fehrmann RS, Terwisscha van Scheltinga AG, et al. MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells. J Pathol. 2019;249:52–64.
68.
Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res. 2013;19:598–609.PubMedCrossRef
69.
Zhang Y, Velez-Delgado A, Mathew E, Li D, Mendez FM, Flannagan K, et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut. 2017;66:124–36.PubMedCrossRef
70.
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res. 2016;22:1499–509.PubMedCrossRef
71.
Mimura K, Kua LF, Shiraishi K, Kee Siang L, Shabbir A, Komachi M, et al. Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-γ treatment. Cancer Sci. 2014;105:1236–44.PubMedPubMedCentralCrossRef
72.
Atefi M, Avramis E, Lassen A, Wong DJ, Robert L, Foulad D, et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res. 2014;20:3446–57.PubMedPubMedCentralCrossRef
73.
Haddadi N, Lin Y, Travis G, Simpson AM, Nassif NT, McGowan EM. PTEN/PTENP1: “regulating the regulator of RTK-dependent PI3K/Akt signalling”, new targets for cancer therapy. Mol Cancer. 2018;17:37.PubMedPubMedCentralCrossRef
74.
Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2:361–70.PubMedPubMedCentralCrossRef
75.
Kim YB, Ahn JM, Bae WJ, Sung CO, Lee D. Functional loss of ARID1A is tightly associated with high PD-L1 expression in gastric cancer. Int J Cancer. 2019;145:916–26.PubMedCrossRef
76.
Suh KJ, Sung JH, Kim JW, Han SH, Lee HS, Min A, et al. EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release. Oncotarget. 2017;8:63901–10.PubMedPubMedCentralCrossRef
77.
Huang TY, Chang TC, Chin YT, Pan YS, Chang WJ, Liu FC, et al. NDAT targets PI3K-mediated PD-L1 upregulation to reduce proliferation in gefitinib-resistant colorectal cancer. Cells. 2020;9:1830.PubMedCentralCrossRef
78.
Fiedler M, Schulz D, Piendl G, Brockhoff G, Eichberger J, Menevse AN, et al. Buparlisib modulates PD-L1 expression in head and neck squamous cell carcinoma cell lines. Exp Cell Res. 2020;396:112259.PubMedCrossRef
79.
Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 2016;76:227–38.PubMedCrossRef
80.
Song TL, Nairismägi ML, Laurensia Y, Lim JQ, Tan J, Li ZM, et al. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood. 2018;132:1146–58.PubMedPubMedCentralCrossRef
81.
Ikeda S, Okamoto T, Okano S, Umemoto Y, Tagawa T, Morodomi Y, et al. PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol. 2016;11:62–71.PubMedCrossRef
82.
Shen M, Xu Z, Xu W, Jiang K, Zhang F, Ding Q, et al. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer Res. 2019;38:149.PubMedPubMedCentralCrossRef
83.
Chen M, Pockaj B, Andreozzi M, Barrett MT, Krishna S, Eaton S, et al. JAK2 and PD-L1 amplification enhance the dynamic expression of PD-L1 in triple-negative breast cancer. Clin Breast Cancer. 2018;18:e1205–15.PubMedCrossRef
84.
Bi XW, Wang H, Zhang WW, Wang JH, Liu WJ, Xia ZJ, et al. PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J Hematol Oncol. 2016;9:109.PubMedPubMedCentralCrossRef
85.
Wang W, Chapman NM, Zhang B, Li M, Fan M, Laribee RN, et al. Upregulation of PD-L1 via HMGB1-activated IRF3 and NF-κB contributes to UV radiation-induced immune suppression. Cancer Res. 2019;79:2909–22.PubMedPubMedCentralCrossRef
86.
Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Mol Cell. 2019;73(22–35):e6.
87.
Xu D, Li J, Li RY, Lan T, Xiao C, Gong P. PD-L1 expression is regulated by NF-κB during EMT signaling in gastric carcinoma. Onco Targets Ther. 2019;12:10099–105.PubMedPubMedCentralCrossRef
88.
Li H, Xia JQ, Zhu FS, Xi ZH, Pan CY, Gu LM, et al. LPS promotes the expression of PD-L1 in gastric cancer cells through NF-κB activation. J Cell Biochem. 2018;119:9997–10004.PubMedCrossRef
89.
Bouillez A, Rajabi H, Jin C, Samur M, Tagde A, Alam M, et al. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene. 2017;36:4037–46.PubMedPubMedCentralCrossRef
90.
Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, et al. Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci U S A. 2019;116:4326–35.PubMedPubMedCentralCrossRef
91.
92.
Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–74.CrossRefPubMed
93.
Sellam LS, Zappasodi R, Chettibi F, Djennaoui D, Yahi-Ait Mesbah N, Amir-Tidadini ZC, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690:108479.PubMedCrossRef
94.
Meng L, Cheng Y, Tong X, Gan S, Ding Y, Zhang Y, et al. Tumor oxygenation and hypoxia inducible factor-1 functional inhibition via a reactive oxygen species responsive nanoplatform for enhancing radiation therapy and abscopal effects. ACS Nano. 2018;12:8308–22.PubMedCrossRef
95.
96.
Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352:227–31.PubMedPubMedCentralCrossRef
97.
Liang MQ, Yu FQ, Chen C. C-Myc regulates PD-L1 expression in esophageal squamous cell carcinoma. Am J Transl Res. 2020;12:379–88.PubMedPubMedCentral
98.
Kim EY, Kim A, Kim SK, Chang YS. MYC expression correlates with PD-L1 expression in non-small cell lung cancer. Lung Cancer. 2017;110:63–7.PubMedCrossRef
99.
Pan Y, Fei Q, Xiong P, Yang J, Zhang Z, Lin X, et al. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology. 2019;8:e1581529.PubMedPubMedCentralCrossRef
100.
Zou J, Zhuang M, Yu X, Li N, Mao R, Wang Z, et al. MYC inhibition increases PD-L1 expression induced by IFN-γ in hepatocellular carcinoma cells. Mol Immunol. 2018;101:203–9.PubMedCrossRef
101.
Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell. 2019;36(483–97):e15.
102.
103.
Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res. 2015;21:4014–21.PubMedCrossRef
104.
Shen J, Li S, Medeiros LJ, Lin P, Wang SA, Tang G, et al. PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol. 2020;33:324–33.PubMedCrossRef
105.
Drilon A, Cappuzzo F, Ou SI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12:15–26.PubMedCrossRef
106.
Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018;18:341–58.PubMedCrossRef
107.
Albitar M, Sudarsanam S, Ma W, Jiang S, Chen W, Funari V, et al. Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer. Oncotarget. 2018;9:13682–93.PubMedPubMedCentralCrossRef
108.
Demuth C, Andersen MN, Jakobsen KR, Madsen AT, Sørensen BS. Increased PD-L1 expression in erlotinib-resistant NSCLC cells with MET gene amplification is reversed upon MET-TKI treatment. Oncotarget. 2017;8:68221–9.PubMedPubMedCentralCrossRef
109.
Ahn HK, Kim S, Kwon D, Koh J, Kim YA, Kim K, et al. MET receptor tyrosine kinase regulates the expression of co-stimulatory and co-inhibitory molecules in tumor cells and contributes to PD-L1-mediated suppression of immune cell function. Int J Mol Sci. 2019;20:4287.PubMedCentralCrossRef
110.
Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol Cancer. 2019;18:165.PubMedPubMedCentralCrossRef
111.
112.
Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 2016;16:2829–37.PubMedPubMedCentralCrossRef
113.
Hogg SJ, Vervoort SJ, Deswal S, Ott CJ, Li J, Cluse LA, et al. BET-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand PD-L1. Cell Rep. 2017;18:2162–74.PubMedPubMedCentralCrossRef
114.
Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017;8:1751.PubMedPubMedCentralCrossRef
115.
116.
Ashizawa M, Okayama H, Ishigame T, Thar Min AK, Saito K, Ujiie D, et al. miRNA-148a-3p regulates immunosuppression in DNA mismatch repair-deficient colorectal cancer by targeting PD-L1. Mol Cancer Res. 2019;17:1403–13.PubMedCrossRef
117.
118.
Anastasiadou E, Stroopinsky D, Alimperti S, Jiao AL, Pyzer AR, Cippitelli C, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia. 2019;33:132–47.PubMedCrossRef
119.
Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014;5:5241.PubMedCrossRef
120.
Sun C, Lan P, Han Q, Huang M, Zhang Z, Xu G, et al. Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat Commun. 2018;9:1241.PubMedPubMedCentralCrossRef
121.
Jia L, Xi Q, Wang H, Zhang Z, Liu H, Cheng Y, et al. miR-142-5p regulates tumor cell PD-L1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun. 2017;488:425–31.PubMedCrossRef
122.
Xu S, Tao Z, Hai B, Liang H, Shi Y, Wang T, et al. miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun. 2016;7:11406.PubMedPubMedCentralCrossRef
123.
124.
Qu F, Ye J, Pan X, Wang J, Gan S, Chu C, et al. MicroRNA-497-5p down-regulation increases PD-L1 expression in clear cell renal cell carcinoma. J Drug Target. 2019;27:67–74.PubMedCrossRef
125.
Xie WB, Liang LH, Wu KG, Wang LX, He X, Song C, et al. MiR-140 expression regulates cell proliferation and targets PD-L1 in NSCLC. Cell Physiol Biochem. 2018;46:654–63.PubMedCrossRef
126.
Wang X, Li J, Dong K, Lin F, Long M, Ouyang Y, et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal. 2015;27:443–52.PubMedCrossRef
127.
Liu J, Fan L, Yu H, Zhang J, He Y, Feng D, et al. Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology. 2019;70:241–58.PubMed
128.
Liu Z, Wen J, Wu C, Hu C, Wang J, Bao Q, et al. MicroRNA-200a induces immunosuppression by promoting PTEN-mediated PD-L1 upregulation in osteosarcoma. Aging (Albany NY). 2020;12:1213–36.CrossRef
129.
Yao X, Tu Y, Xu Y, Guo Y, Yao F, Zhang X. Endoplasmic reticulum stress-induced exosomal miR-27a-3p promotes immune escape in breast cancer via regulating PD-L1 expression in macrophages. J Cell Mol Med. 2020;24:9560–73.PubMedPubMedCentralCrossRef
130.
Sheng Q, Zhang Y, Wang Z, Ding J, Song Y, Zhao W. Cisplatin-mediated down-regulation of miR-145 contributes to up-regulation of PD-L1 via the c-Myc transcription factor in cisplatin-resistant ovarian carcinoma cells. Clin Exp Immunol. 2020;200:45–52.PubMedCrossRef
131.
Dong P, Xiong Y, Yu J, Chen L, Tao T, Yi S, et al. Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer. Oncogene. 2018;37:5257–68.PubMedPubMedCentralCrossRef
132.
Tang D, Zhao D, Wu Y, Yao R, Zhou L, Lu L, et al. The miR-3127-5p/p-STAT3 axis up-regulates PD-L1 inducing chemoresistance in non-small-cell lung cancer. J Cell Mol Med. 2018;22:3847–56.PubMedCentralCrossRefPubMed
133.
Yoon CJ, Chang MS, Kim DH, Kim W, Koo BK, Yun SC, et al. Epstein-Barr virus-encoded miR-BART5-5p upregulates PD-L1 through PIAS3/pSTAT3 modulation, worsening clinical outcomes of PD-L1-positive gastric carcinomas. Gastric Cancer. 2020;23:780–95.PubMedCrossRef
134.
Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, et al. Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature. 2016;534:402–6.PubMedCrossRef
135.
Coelho MA, de Carné TS, Rana S, Zecchin D, Moore C, Molina-Arcas M, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity. 2017;47(1083–99):e6.
136.
Yang K, Zhou J, Chen Y, Chen Y, Chen L, Zhang P, et al. Angiotensin II contributes to intratumoral immunosuppressionvia induction of PD-L1 expression in non-small cell lung carcinoma. Int Immunopharmacol. 2020;84:106507.PubMedCrossRef
137.
Wu Z, Huang R, Yuan L. Crosstalk of intracellular post-translational modifications in cancer. Arch Biochem Biophys. 2019;676:108138.PubMedCrossRef
138.
Burr ML, Sparbier CE, Chan YC, Williamson JC, Woods K, Beavis PA, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017;549:101–5.PubMedPubMedCentralCrossRef
139.
Shaid S, Brandts CH, Serve H, Dikic I. Ubiquitination and selective autophagy. Cell Death Differ. 2013;20:21–30.PubMedCrossRef
140.
Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017;549:106–10.PubMedPubMedCentralCrossRef
141.
Zhang J, Bu X, Wang H, Zhu Y, Geng Y, Nihira NT, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature. 2018;553:91–5.PubMedCrossRef
142.
143.
Chan LC, Li CW, Xia W, Hsu JM, Lee HH, Cha JH, et al. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019;129:3324–38.PubMedPubMedCentralCrossRef
144.
Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell. 2018;71(606–20):e7.
145.
Li CW, Lim SO, Xia W, Lee HH, Chan LC, Kuo CW, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632.PubMedPubMedCentralCrossRef
146.
Li H, Li CW, Li X, Ding Q, Guo L, Liu S, et al. MET inhibitors promote liver tumor evasion of the immune response by stabilizing PDL1. Gastroenterology. 2019;156(1849–61):e13.
147.
Veillon L, Fakih C, Abou-El-Hassan H, Kobeissy F, Mechref Y. Glycosylation changes in brain cancer. ACS Chem Neurosci. 2018;9:51–72.PubMedCrossRef
148.
Shi X, Zhang D, Li F, Zhang Z, Wang S, Xuan Y, et al. Targeting glycosylation of PD-1 to enhance CAR-T cell cytotoxicity. J Hematol Oncol. 2019;12:127.PubMedPubMedCentralCrossRef
149.
Hsu JM, Xia W, Hsu YH, Chan LC, Yu WH, Cha JH, et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun. 2018;9:1908.PubMedPubMedCentralCrossRef
150.
D'Arrigo P, Russo M, Rea A, Tufano M, Guadagno E, Del Basso De Caro ML, et al. A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma. Oncotarget. 2017;8:68291–304.
151.
Yang Y, Hsu JM, Sun L, Chan LC, Li CW, Hsu JL, et al. Palmitoylation stabilizes PD-L1 to promote breast tumor growth. Cell Res. 2019;29:83–6.PubMedCrossRef
152.
Yao H, Lan J, Li C, Shi H, Brosseau JP, Wang H, et al. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng. 2019;3:306–17.PubMedCrossRef
153.
Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13:1138–45.PubMedPubMedCentralCrossRef
Metadata
Title
Regulation of PD-L1 expression in the tumor microenvironment
Authors
Ming Yi
Mengke Niu
Linping Xu
Suxia Luo
Kongming Wu
Publication date
01-12-2021
Publisher
BioMed Central
Keywords
NSCLC
NSCLC
Published in
Journal of Hematology & Oncology / Issue 1/2021
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-01027-5

Other articles of this Issue 1/2021

Journal of Hematology & Oncology 1/2021 Go to the issue

Review

Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia

Research

Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells

Letter to the Editor

Multi-dimensional fragmentomic assay for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma

Correction

Correction to: Anti-PD-1 antibodies as a salvage therapy for patients with diffuse large B cell lymphoma who progressed/relapsed after CART19/20 therapy

Letter to the Editor

Low titers of SARS-CoV-2 neutralizing antibodies after first vaccination dose in cancer patients receiving checkpoint inhibitors

Research

Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits