Mechanisms Controlling PD-L1 Expression in Cancer

The engagement of programmed cell death protein 1 (PD-1; encoded by the PDCD1 gene) receptor expressed on activated T cells and its ligand, programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), is a major co-inhibitory checkpoint signaling that controls T cell activities. Various types of cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T cell immunity. Blocking the PD-L1/PD-1 pathway has consistently shown remarkable anti-tumor effects in patients with advanced cancers and is recognized as the gold standard for developing new immune checkpoint blockade (ICB) and combination therapies. However, the response rates of anti-PD-L1 have been limited in several solid tumors. Therefore, furthering our understanding of the regulatory mechanisms of PD-L1 can bring substantial benefits to patients with cancer by improving the efficacy of current PD-L1/PD-1 blockade or other ICBs. In this review, we provide current knowledge of PD-L1 regulatory mechanisms at the transcriptional, posttranscriptional, post-translational, and extracellular levels, and discuss the implications of these findings in cancer diagnosis and immunotherapy. The engagement of programmed cell death protein 1 (PD-1; encoded by the PDCD1 gene) receptor expressed on activated T cells and its ligand, programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), is a major co-inhibitory checkpoint signaling that controls T cell activities. Various types of cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T cell immunity. Blocking the PD-L1/PD-1 pathway has consistently shown remarkable anti-tumor effects in patients with advanced cancers and is recognized as the gold standard for developing new immune checkpoint blockade (ICB) and combination therapies. However, the response rates of anti-PD-L1 have been limited in several solid tumors. Therefore, furthering our understanding of the regulatory mechanisms of PD-L1 can bring substantial benefits to patients with cancer by improving the efficacy of current PD-L1/PD-1 blockade or other ICBs. In this review, we provide current knowledge of PD-L1 regulatory mechanisms at the transcriptional, posttranscriptional, post-translational, and extracellular levels, and discuss the implications of these findings in cancer diagnosis and immunotherapy. T cell immunity is critical for maintaining our body's homeostasis by selectively recognizing and eliminating pathogens and abnormal cells, including cancer cells. However, hyperactivation of uncontrolled T cells may also attack normal cells (Zhang and Bevan, 2011Zhang N. Bevan M.J. CD8(+) T cells: foot soldiers of the immune system.Immunity. 2011; 35: 161-168Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar). To prevent such autoimmune reactions, co-inhibitory immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1; encoded by the PDCD1 gene), and programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), maintain an intricate regulation of T cell activities in normal physiological conditions (Francisco et al., 2010Francisco L.M. Sage P.T. Sharpe A.H. The PD-1 pathway in tolerance and autoimmunity.Immunol. Rev. 2010; 236: 219-242Crossref PubMed Scopus (1549) Google Scholar). In many human cancers, including renal cell carcinoma (RCC), breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer (NSCLC), papillary thyroid cancer, and testicular cancer (Thompson et al., 2004Thompson R.H. Gillett M.D. Cheville J.C. Lohse C.M. Dong H. Webster W.S. Krejci K.G. Lobo J.R. Sengupta S. Chen L. et al.Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.Proc. Natl. Acad. Sci. USA. 2004; 101: 17174-17179Crossref PubMed Scopus (694) Google Scholar), high PD-L1 expression is detected and associated with poor prognosis (Ohaegbulam et al., 2015Ohaegbulam K.C. Assal A. Lazar-Molnar E. Yao Y. Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway.Trends Mol. Med. 2015; 21: 24-33Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar). Indeed, the binding between PD-L1 on cancer cells with PD-1 on tumor-infiltrating T cells (TILs) activates Src homology region 2 domain-containing phosphatases (SPH2s), leading to suppression of the T cell receptor (TCR) pathway and inhibition of T cell activity. Moreover, interruption of immune surveillance promotes cancer cell survival by exploiting PD-L1/PD-1 signaling (Schildberg et al., 2016Schildberg F.A. Klein S.R. Freeman G.J. Sharpe A.H. Coinhibitory pathways in the B7-CD28 ligand-receptor family.Immunity. 2016; 44: 955-972Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar). In addition to cancer cells, multiple types of host cells in the tumor microenvironment (TME) and lymph nodes, including dendritic cells, macrophages, fibroblasts, and T cells, also express PD-L1 to reduce anti-tumor immunity (Curiel et al., 2003Curiel T.J. Wei S. Dong H. Alvarez X. Cheng P. Mottram P. Krzysiek R. Knutson K.L. Daniel B. Zimmermann M.C. et al.Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.Nat. Med. 2003; 9: 562-567Crossref PubMed Scopus (1041) Google Scholar, Zou et al., 2016Zou W. Wolchok J.D. Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.Sci. Transl. Med. 2016; 8: 328rv4Crossref PubMed Scopus (1473) Google Scholar). Recently, Tang et al. reported that PD-L1 is upregulated by interferon γ (IFN-γ) on antigen-presenting cells (APCs) in the TME and lymph nodes to inhibit T cell activation (Tang et al., 2018Tang H. Liang Y. Anders R.A. Taube J.M. Qiu X. Mulgaonkar A. Liu X. Harrington S.M. Guo J. Xin Y. et al.PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression.J. Clin. Invest. 2018; 128: 580-588Crossref PubMed Scopus (305) Google Scholar). Meanwhile, Lin et al. also reported that the efficacy of PD-1 antibody treatment alone or in combination with CTLA-4 antibody is correlated with the expression of PD-L1 on dendritic cells and macrophages in the tumor region and tumor-draining lymph nodes of patients with ovarian cancer or melanoma (Lin et al., 2018Lin H. Wei S. Hurt E.M. Green M.D. Zhao L. Vatan L. Szeliga W. Herbst R. Harms P.W. Fecher L.A. et al.Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression.J. Clin. Invest. 2018; 128: 805-815Crossref PubMed Scopus (313) Google Scholar). Based on the above findings, therapeutic antibodies against PD-L1 (e.g., atezolizumab, avelumab, and durvalumab) and PD-1 (e.g., nivolumab, pembrolizumab, and cemiplimab) were developed and have demonstrated promising results in clinical trials for various types of cancer (Gong et al., 2018Gong J. Chehrazi-Raffle A. Reddi S. Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations.J. Immunother. Cancer. 2018; 6: 8Crossref PubMed Scopus (724) Google Scholar). Specifically, blocking the PD-L1/PD-1 signaling axis by antibody reactivates the exhausted immune cells in the TME and eliminates cancer cells. This therapeutic strategy normalizes the imbalanced anti-tumor immunity and has achieved a 10%–40% response in the clinic (Zou et al., 2016Zou W. Wolchok J.D. Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.Sci. Transl. Med. 2016; 8: 328rv4Crossref PubMed Scopus (1473) Google Scholar). Currently, PD-L1 and PD-1 antibodies are approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple cancer types, including melanoma, small cell lung cancer (SCLC), NSCLC, RCC, head and neck squamous cell carcinomas (HNSCCs), classical Hodgkin lymphoma (cHL), and Merkel cell carcinoma. Based on the promising therapeutic outcomes from anti-PD-1/PD-L1 therapy, PD-L1 has become a key protein in immuno-oncology, and its functions and regulatory mechanisms are being intensively studied. In addition, the expression of PD-L1 is intricately regulated by various processes, such as gene transcription, post-transcriptional and post-translational modifications (PTMs), and exosomal transport. Therefore, it is important to broaden our understanding of the regulation of PD-L1 expression to improve the efficacy of current immune checkpoint blockade (ICB) and advance cancer immunotherapy. Aberrant signaling pathways and genomic mutations drive the formation of tumors. During cell transformation and tumorigenesis, upregulation of PD-L1 by these oncogenic pathways or gene mutations attenuates the activity of immune cells, allowing cancer cells to escape immunosurveillance and enhance their survival and metastatic potential. The TME provides a further enhanced niche for cancer immune escape by augmenting PD-L1 expression induced by pro-inflammatory cytokines, such as IFNγ, tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) (Chan et al., 2019Chan L.C. Li C.W. Xia W. Hsu J.M. Lee H.H. Cha J.H. Wang H.L. Yang W.H. Yen E.Y. Chang W.C. et al.IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion.J. Clin. 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Below, we discuss the genomic alterations, and transcriptional and post-transcriptional mechanisms of PD-L1 in cancer cells and TME as well as their potential as biomarkers to improve and enhance the response rate of PD-L1/PD-1 therapy (Figure 1).Table 1Regulatory Mechanism of PD-L1 in the TMEStage of RegulationKey Regulator/RegionRegulatory MechanismPD-L1 LevelPotential/Proposed Therapeutic StrategiesReferencesGenomic alteration/rearrangements9p24.1PD-L1 amplifications and translocations in genomeUpCancer Genome Atlas Research Network, 2014Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3948) Google Scholar, Green et al., 2010Green M.R. Monti S. Rodig S.J. Juszczynski P. Currie T. O'Donnell E. Chapuy B. Takeyama K. Neuberg D. 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Med. 2007; 13: 84-88Crossref PubMed Scopus (1056) Google ScholarPost-transcriptional levelEnhanced RNA stabilityRAS signaling can upregulate PD-L1 mRNA stability via modulation of the AU-rich element-binding protein TTPUpCoelho et al., 2017Coelho M.A. de Carne Trecesson S. Rana S. Zecchin D. Moore C. Molina-Arcas M. East P. Spencer-Dene B. Nye E. Barnouin K. et al.Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA.Immunity. 2017; 47: 1083-1099.e1086Abstract Full Text Full Text PDF PubMed Scopus (349) Google ScholarPTM (phosphorylation)GSK3βPhosphorylation of PD-L1 at T180 and S184 recruits β-TrCP for degradation. PARP or c-Met inhibitors enhance PD-L1 expression by blocking GSK3βDownBlocking PRAP or c-Met to increase the therapeutic effect of anti-PD-1/PD-L1 antibodyJiao et al., 2017Jiao S. Xia W. Yamaguchi H. Wei Y. Chen M.K. Hsu J.M. Hsu J.L. Yu W.H. Du Y. 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