Regulation of post-translational modification of PD-L1 and associated opportunities for novel small-molecule therapeutics

References

• Grakoui A, Bromley SK, Sumen C, et al. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999;285:221–227. doi:10.1126/science.285.5425.221
   PubMed Web of Science ®Google Scholar
• Monks CRF, Freiberg BA, Kupfer H, et al. Three-dimensional segregation of supramolecular activation clusters in T-cells. Nature. 1998;395:82–86. doi:10.1038/25764
   PubMed Web of Science ®Google Scholar
• Saito T, Yokosuka T, Hashimoto-Tane A, et al. Dynamic regulation of T-cell activation and co-stimulation through TCR-microclusters. FEBS Lett. 2010;584:4865–4871. doi:10.1016/j.febslet.2010.11.036
   PubMed Web of Science ®Google Scholar
• Cadranel J, Canellas A, Matton L, et al. Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer. Eur Respir Rev. 2019;28:190058. doi:10.1183/16000617.0058-2019
   PubMed Web of Science ®Google Scholar
• Isaacsson Velho P, Antonarakis ES, Isaacsson Velho P, et al. PD-1/PD-L1 pathway inhibitors in advanced prostate cancer. Expert Rev Clinical Pharmacology. 2018;11:475–486. doi:10.1080/17512433.2018.1464388
   PubMed Web of Science ®Google Scholar
• Tu X, Qin B, Zhang Y, et al. PD-L1 (B7–H1) competes with the RNA exosome to regulate the DNA damage response and can be targeted to sensitize to radiation or chemotherapy. Molecular Cell. 2019;74:1215–1226.e4. doi:10.1016/j.molcel.2019.04.005
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the Pd-1 immunoinhibitory receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. J Experimental Medicine. 2000;192:1027–1034. doi:10.1084/jem.192.7.1027
   PubMed Web of Science ®Google Scholar
• Chen DS, Irving BA, Hodi FS, et al. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–6587. doi:10.1158/1078-0432.CCR-12-1362
   PubMed Web of Science ®Google Scholar
• Chen L, Han X, Chen L, et al. Anti–PD-1/PD-L1 therapy of human cancer: past, present and future. J Clin Invest. 2015;125:3384–3391. doi:10.1172/JCI80011
   PubMed Web of Science ®Google Scholar
• Zak KM, Kitel R, Przetocka S, et al. Structure of the complex of human programmed death 1, PD-1 and its ligand PD-L1. Structure. 2015;23:2341–2348. doi:10.1016/j.str.2015.09.010
   PubMed Web of Science ®Google Scholar
• He J, Hu Y, Hu M, et al. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep. 2015;5:13110. doi:10.1038/srep13110
   PubMed Web of Science ®Google Scholar
• Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. doi:10.1038/nm730
   PubMed Web of Science ®Google Scholar
• Magiera-Mularz K, Skalniak L, Zak KM, et al. Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint. Angew Chem Int Ed. 2017;56:13732–13735. doi:10.1002/anie.201707707
   PubMed Web of Science ®Google Scholar
• Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383:1218–1230. doi:10.1056/NEJMoa2002788
   PubMed Web of Science ®Google Scholar
• Mu L, Song Y, Zhao K, et al. SHR-1316, an anti-PD-L1 antibody, plus chemotherapy as the first-line treatment for advanced esophageal squamous cell carcinoma: a multicentre, phase 2 study. Thoracic Cancer. 2021;12:1373–1381. doi:10.1111/1759-7714.13913
   PubMed Web of Science ®Google Scholar
• Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res. 2015;21:976–984. doi:10.1158/1078-0432.CCR-14-1187
   PubMed Web of Science ®Google Scholar
• Abdollahi A, Folkman J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resistance Updates. 2010;13:16–28. doi:10.1016/j.drup.2009.12.001
   PubMed Web of Science ®Google Scholar
• Pan C, Yang H, Lu Y, et al. Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation. Eur J Medicinal Chemistry. 2021;213:113170. doi:10.1016/j.ejmech.2021.113170
   PubMed Web of Science ®Google Scholar
• Wu Q, Jiang L, Li S, et al. Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway. Acta Pharmacol Sin. 2021;42:1–9. doi:10.1038/s41401-020-036
   PubMed Web of Science ®Google Scholar
• Maher CM, Thomas JD, Haas DA, et al. Small-molecule sigma1 modulator induces autophagic degradation of PD-L1. Mol Cancer Res. 2018;16:243–255. doi:10.1158/1541-7786.MCR-17-0166
   PubMed Web of Science ®Google Scholar
• Schrock JM, Spino CM, Longen CG, et al. Sequential cytoprotective responses to sigma1 ligand–induced endoplasmic reticulum stress. Mol Pharmacol. 2013;84:751–762. doi:10.1124/mol.113.087809
   PubMed Web of Science ®Google Scholar
• Zhang J, Bu X, Wang H, et al. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature. 2018;553:91–95. doi:10.1038/nature25015
   PubMed Web of Science ®Google Scholar
• Cha J-H, Yang W-H, Xia W, et al. Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Molecular Cell. 2018;71:606–620.e7. doi:10.1016/j.molcel.2018.07.030
   PubMed Web of Science ®Google Scholar
• Yamaguchi H, Hsu J-M, Yang W-H, et al. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol. 2022;19:287–305. doi:10.1038/s41571-022-00601-9
   PubMed Web of Science ®Google Scholar
• Lee JM, Hammarén HM, Savitski MM, et al. Control of protein stability by post-translational modifications. Nat Commun. 2023;14:201. doi:10.1038/s41467-023-35795-8
   PubMed Web of Science ®Google Scholar
• Yao H, Lan J, Li C, et al. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng. 2019;3:306–317. doi:10.1038/s41551-019-0375-6
   PubMed Web of Science ®Google Scholar
• Li C-W, Lim S-O, Xia W, et al. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016;7:12632. doi:10.1038/ncomms12632
   PubMed Web of Science ®Google Scholar
• Spiro RG. Role of N -linked polymannose oligosaccharides in targeting glycoproteins for endoplasmic reticulum-associated degradation. Cellular Molecular Life Sciences (CMLS). 2004;61:1025–1041. doi:10.1007/s00018-004-4037-8
   PubMed Web of Science ®Google Scholar
• Molinari M, Helenius A. Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells. Nature. 1999;402:90–93. doi:10.1038/47062
   PubMed Web of Science ®Google Scholar
• Sitia R, Braakman I. Quality control in the endoplasmic reticulum protein factory. Nature. 2003;426:891–894. doi:10.1038/nature02262
   PubMed Web of Science ®Google Scholar
• Fiedler K, Simons K. The role of n-glycans in the secretory pathway. Cell. 1995;81:309–312. doi:10.1016/0092-8674(95)90380-1
   PubMed Web of Science ®Google Scholar
• Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem. 2004;73:1019–1049. doi:10.1146/annurev.biochem.73.011303.073752
   PubMed Web of Science ®Google Scholar
• Helenius A, Aebi M. Intracellular functions of N-linked glycans. Science. 2001;291:2364–2369. doi:10.1126/science.291.5512.2364
   PubMed Web of Science ®Google Scholar
• Dwek RA. Glycobiology: toward understanding the function of sugars. Chem Rev. 1996;96:683–720. doi:10.1021/cr940283b
   PubMed Web of Science ®Google Scholar
• Skropeta D. The effect of individual N-glycans on enzyme activity. Bioorganic Medicinal Chemistry. 2009;17:2645–2653. doi:10.1016/j.bmc.2009.02.037
   PubMed Web of Science ®Google Scholar
• Xu C, Ng DTW. Glycosylation-directed quality control of protein folding. Nat Rev Mol Cell Biol. 2015;16:742–752. doi:10.1038/nrm4073
   PubMed Web of Science ®Google Scholar
• Li C-W, Lim S-O, Chung EM, et al. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell. 2018;33:187–201.e10. doi:10.1016/j.ccell.2018.01.009
   PubMed Web of Science ®Google Scholar
• Hsu J-M, Xia W, Hsu Y-H, et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun. 2018;9:1908. doi:10.1038/s41467-018-04313-6
   PubMed Web of Science ®Google Scholar
• Chan L-C, Li C-W, Xia W, et al. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019;129:3324–3338. doi:10.1172/JCI126022
   PubMed Web of Science ®Google Scholar
• Shi C, Wang Y, Wu M, et al. Promoting antitumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation. Nat Commun. 2022;13:6951. doi:10.1038/s41467-022-34346-x
   PubMed Web of Science ®Google Scholar
• Ma X-M, Luo Y-F, Zeng F-F, et al. TGF-β1-mediated PD-L1 glycosylation contributes to immune escape via c-Jun/STT3A pathway in nasopharyngeal carcinoma. Front Oncol. 2022;12:815437. doi:10.3389/fonc.2022.815437
   PubMed Web of Science ®Google Scholar
• Kim B-G, Malek E, Choi SH, et al. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14:55. doi:10.1186/s13045-021-01053-x
   PubMed Web of Science ®Google Scholar
• D'Arrigo P, Russo M, Rea A, et al. A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma. Oncotarget. 2017;8:68291–68304. doi:10.18632/oncotarget.19309
   PubMedGoogle Scholar
• Gaali S, Kirschner A, Cuboni S, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol. 2015;11:33–37. doi:10.1038/nchembio.1699
   PubMed Web of Science ®Google Scholar
• Kim FJ, Schrock JM, Spino CM, et al. Inhibition of tumor cell growth by Sigma1 ligand mediated translational repression. Biochem Biophys Res Commun. 2012;426:177–182. doi:10.1016/j.bbrc.2012.08.052
   PubMed Web of Science ®Google Scholar
• Liu X, Zhang Y, Han Y, et al. Overexpression of GLT1D1 induces immunosuppression through glycosylation of PD-L1 and predicts poor prognosis in B-cell lymphoma. Molecular Oncology. 2020;14:1028–1044. doi:10.1002/1878-0261.12664
   PubMed Web of Science ®Google Scholar
• Ruan Z, Liang M, Shang L, et al. Shikonin-mediated PD-L1 degradation suppresses immune evasion in pancreatic cancer by inhibiting NF-κB/STAT3 and NF-κB/CSN5 signaling pathways. Pancreatology. 2021;21:630–641. doi:10.1016/j.pan.2021.01.023
   PubMed Web of Science ®Google Scholar
• Verdura S, Cuyàs E, Cortada E, et al. Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity. Aging. 2020;12:8–34. doi:10.18632/aging.102646
   PubMedGoogle Scholar
• Hershko A, Heller H, Elias S, et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification and role in protein breakdown. J Biol Chem. 1983;258:8206–8214. doi:10.1016/S0021-9258(20)82050-X
   PubMed Web of Science ®Google Scholar
• Finley D, Ciechanover A, Varshavsky A. Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. Cell. 1984;37:43–55. doi:10.1016/0092–8674(84)90299-X
   PubMed Web of Science ®Google Scholar
• Burr ML, Sparbier CE, Chan Y-C, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017;549:101–105. doi:10.1038/nature23643
   PubMed Web of Science ®Google Scholar
• Mezzadra R, Sun C, Jae LT, et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017;549:106–110. doi:10.1038/nature23669
   PubMed Web of Science ®Google Scholar
• Deng L, Qian G, Zhang S, et al. Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced β-TrCP degradation. Oncogene. 2019;38:6270–6282. doi:10.1038/s41388-019-0877-4
   PubMed Web of Science ®Google Scholar
• Wu Y, Zhang C, Liu X, et al. ARIH1 signaling promotes antitumor immunity by targeting PD-L1 for proteasomal degradation. Nat Commun. 2021;12:2346. doi:10.1038/s41467-021-22467-8
   PubMed Web of Science ®Google Scholar
• Qian G, Guo J, Vallega KA, et al. Membrane-associated RING-CH 8 functions as a novel PD-L1 E3 ligase to mediate PD-L1 degradation induced by EGFR inhibitors. Molecular Cancer Research. 2021;19:1622–1634. doi:10.1158/1541-7786.MCR-21-147
   PubMed Web of Science ®Google Scholar
• Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98:8554–8559. doi:10.1073/pnas.141230798
   PubMed Web of Science ®Google Scholar
• Liu J, Ma J, Liu Y, et al. PROTACs: a novel strategy for cancer therapy. Semin Cancer Biol. 2020;67:171–179. doi:10.1016/j.semcancer.2020.02.006
   PubMed Web of Science ®Google Scholar
• Ohashi K, Maruvka YE, Michor F, et al. Epidermal growth factor receptor tyrosine kinase inhibitor–resistant disease. JCO. 2013;31:1070–1080. doi:10.1200/JCO.2012.43.3912
   PubMed Web of Science ®Google Scholar
• Pettersson M, Crews CM. PROteolysis TArgeting Chimeras (PROTACs) — past, present and future. Drug Discovery Today: Technologies. 2019;31:15–27. doi:10.1016/j.ddtec.2019.01.002
   PubMedGoogle Scholar
• Wang Y, Zhou Y, Cao S, et al. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC). Bioorganic Chemistry. 2021;111:104833. doi:10.1016/j.bioorg.2021.104833
   PubMed Web of Science ®Google Scholar
• Cheng B, Ren Y, Cao H, et al. Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1. Eur J Medicinal Chemistry. 2020;199:112377. doi:10.1016/j.ejmech.2020.112377
   PubMed Web of Science ®Google Scholar
• Wang K, Dai X, Yu A, et al. Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression. J Exp Clin Cancer Res. 2022;41:289. doi:10.1186/s13046-022-02483-2
   PubMed Web of Science ®Google Scholar
• Dai M-Y, Shi Y-Y, Wang A-J, et al. High-potency PD-1/PD-L1 degradation induced by Peptide-PROTAC in human cancer cells. Cell Death Dis. 2022;13:924; s41419-022-05375-05377. doi:10.1038/s41419-022-05375-7
   PubMed Web of Science ®Google Scholar
• Cotton AD, Nguyen DP, Gramespacher JA, et al. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J Am Chem Soc. 2021;143:593–598. doi:10.1021/jacs.0c10008
   PubMed Web of Science ®Google Scholar
• Lim S-O, Li C-W, Xia W, et al. Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell. 2016;30:925–939. doi:10.1016/j.ccell.2016.10.010
   PubMed Web of Science ®Google Scholar
• Liu C, Yao Z, Wang J, et al. Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway. Cell Death Differ. 2020;27:1765–1781. doi:10.1038/s41418-019-0460-0
   PubMed Web of Science ®Google Scholar
• Wang Y, Sun Q, Mu N, et al. The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells. Cell Commun Signal. 2020;18:112. doi:10.1186/s12964-020-00612-y
   PubMed Web of Science ®Google Scholar
• Kim S, Woo S, Min K, et al. WP1130 enhances TRAIL-induced apoptosis through USP9X-dependent miR-708-mediated downregulation of c-FLIP. Cancers. 2019;11:344. doi:10.3390/cancers11030344
   PubMed Web of Science ®Google Scholar
• Liu H, Chen W, Liang C, et al. WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation. Cancer Lett. 2015;361:218–225. doi:10.1016/j.canlet.2015.03.001
   PubMed Web of Science ®Google Scholar
• Jingjing W, Wenzheng G, Donghua W, et al. Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin-specific peptidase 9, X-linked in oral squamous cell carcinoma. Cancer Medicine. 2018;7:4004–4011. doi:10.1002/cam4.1675
   PubMed Web of Science ®Google Scholar
• Zhu D, Xu R, Huang X, et al. Deubiquitinating enzyme OTUB1 promotes cancer cell immunosuppression via preventing ER-associated degradation of immune checkpoint protein PD-L1. Cell Death Differ. 2021;28:1773–1789. doi:10.1038/s41418-020-00700-z
   PubMed Web of Science ®Google Scholar
• Zhou T, Li J, Zhao P, et al. Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy. Proc Natl Acad Sci USA. 2015;112:15666–15671. doi:10.1073/pnas.1518368112
   PubMed Web of Science ®Google Scholar
• Chen X, Ma H, Wang Z, et al. EZH2 palmitoylation mediated by ZDHHC5 in p53-mutant glioma drives malignant development and progression. Cancer Res. 2017;77:4998–5010. doi:10.1158/0008-5472.CAN-17-1139
   PubMed Web of Science ®Google Scholar
• Runkle KB, Kharbanda A, Stypulkowski E, et al. Inhibition of DHHC20-mediated EGFR palmitoylation creates a dependence on EGFR signaling. Molecular Cell. 2016;62:385–396. doi:10.1016/j.molcel.2016.04.003
   PubMed Web of Science ®Google Scholar
• Coleman DT, Gray AL, Kridel SJ, et al. Palmitoylation regulates the intracellular trafficking and stability of c-Met. Oncotarget. 2016;7:32664–32677. doi:10.18632/oncotarget.8706
   PubMedGoogle Scholar
• Ko P, Dixon SJ. Protein palmitoylation and cancer. EMBO Reports. 2018;19:e46666. doi:10.15252/embr.201846666
   PubMed Web of Science ®Google Scholar
• Yeste-Velasco M, Linder ME, Lu Y-J. Protein S-palmitoylation and cancer. Biochim Biophys Acta. 2015;1856:107–120. doi:10.1016/j.bbcan.2015.06.004
   PubMed Web of Science ®Google Scholar
• Sharma C, Wang H-X, Li Q, et al. Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence. Cancer Res. 2017;77:6880–6890.
   PubMed Web of Science ®Google Scholar
• Yang Y, Hsu J-M, Sun L, et al. Palmitoylation stabilizes PD-L1 to promote breast tumor growth. Cell Res. 2019;29:83–86. doi:10.1158/0008-5472.CAN-17-1536
   PubMed Web of Science ®Google Scholar
• Davda D, El Azzouny MA, Tom CTMB, et al. Profiling targets of the irreversible palmitoylation inhibitor 2-bromopalmitate. ACS Chem Biol. 2013;8:1912–1917. doi:10.1021/cb400380s
   PubMed Web of Science ®Google Scholar
• DeJesus G, Bizzozero OA. Effect of 2-fluoropalmitate, cerulenin and tunicamycin on the palmitoylation and intracellular translocation of myelin proteolipid protein. Neurochem Res .2002 ;27:1669–1675. doi:10.1023/a:1021643229028
   PubMed Web of Science ®Google Scholar
• Hong JY, Malgapo MIP, Liu Y, et al. High-throughput enzyme assay for screening inhibitors of the ZDHHC3/7/20 acyltransferases. ACS Chem Biol. 2021;16:1318–1324. doi:10.1021/acschembio.1c00258
   PubMed Web of Science ®Google Scholar
• Azizi S-A, Lan T, Delalande C, et al. Development of an acrylamide-based inhibitor of protein S-acylation. ACS Chem Biol. 2021;16:1546–1556. doi:10.1021/acschembio.1c00405
   PubMed Web of Science ®Google Scholar
• Ducker CE, Griffel LK, Smith RA, et al. Discovery and characterization of inhibitors of human palmitoyl acyltransferases. Mol Cancer Ther. 2006;5:1647–1659. doi:10.1158/1535-7163.MCT-06-0114
   PubMed Web of Science ®Google Scholar
• Jennings BC, Nadolski MJ, Ling Y, et al. 2-Bromopalmitate and 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one inhibit DHHC-mediated palmitoylation in vitro. J Lipid Res. 2009;50:233–242. doi:10.1194/jlr.M800270-JLR200
   PubMed Web of Science ®Google Scholar
• Cohen P. The origins of protein phosphorylation. Nat Cell Biol. 2002;4:E127–E130. doi:10.1038/ncb0502-e127
   PubMed Web of Science ®Google Scholar
• Dai X, Bu X, Gao Y, et al. Energy status dictates PD-L1 protein abundance and antitumor immunity to enable checkpoint blockade. Molecular Cell. 2021;81:2317–2331.e6. doi:10.1016/j.molcel.2021.03.037
   PubMed Web of Science ®Google Scholar
• Zhang R, Yang Y, Dong W, et al. D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1. Proc Natl Acad Sci USA. 2022;119:e2114851119. doi:10.1073/pnas.2114851119
   PubMed Web of Science ®Google Scholar
• Zhao X, Wei Y, Chu Y-Y, et al. Phosphorylation and stabilization of PD-L1 by CK2 suppresses dendritic cell function. Cancer Res. 2022;82:2185–2195. doi:10.1158/0008-5472.CAN-21-2300
   PubMed Web of Science ®Google Scholar
• Zhang X, Huang X, Xu J, et al. NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1. Nat Commun. 2021;12:4536. doi:10.1038/s41467-021-24769-3
   PubMed Web of Science ®Google Scholar
• Inuzuka H, Gao D, Finley LWS, et al. Acetylation-dependent regulation of Skp2 function. Cell. 2012;150:179–193. doi:10.1016/j.cell.2012.05.038
   PubMed Web of Science ®Google Scholar
• Xu P, Xiong W, Lin Y, et al. Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression. Cell Death Dis. 2021;12:779. doi:10.1038/s41419-021-04047-2
   PubMed Web of Science ®Google Scholar
• Pulya S, Himaja A, Paul M, et al. Selective HDAC3 inhibitors with potent in vivo antitumor efficacy against triple-negative breast cancer. J Med Chem. 2023;66:12033–12058. doi:10.1021/acs.jmedchem.3c00614
   PubMedGoogle Scholar
• Gao Y, Nihira NT, Bu X, et al. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol. 2020;22:1064–1075. doi:10.1038/s41556-020-0562-4
   PubMed Web of Science ®Google Scholar
• Yu J, Zhuang A, Gu X, et al. Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis. Cell Discov. 2023;9:33. doi:10.1038/s41421-023-00521-7
   PubMed Web of Science ®Google Scholar
• Lanouette S, Mongeon V, Figeys D, et al. The functional diversity of protein lysine methylation. Molecular Systems Biology. 2014;10:724. doi:10.1002/msb.134974
   PubMed Web of Science ®Google Scholar
• Biggar KK, Li SS-C. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol. 2015;16:5–17. doi:10.1038/nrm3915
   PubMed Web of Science ®Google Scholar
• Huang C, Ren S, Chen Y, et al. PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance. Sci Adv. 2023;9:eade4186. doi:10.1126/sciadv.ade4186
   PubMed Web of Science ®Google Scholar