{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T21:05:31Z","timestamp":1788210331162,"version":"build-2803163510"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Programmed cell death protein 1 (PD-1)\/PD-ligand (L)1, the immune checkpoint inhibitors have emerged as a promising strategy for the treatment of various diseases including chronic liver diseases (CLDs) such as hepatitis, liver injury and hepatocellular carcinoma (HCC). The role of PD-1\/PD-L1 has been widely inspected in the treatment of viral hepatitis and HCC. PD-1 is known to play a crucial role in inhibiting immunological responses and stimulates self-tolerance by regulating the T-cell activity. Further, it promotes apoptosis of antigen-specific T-cells while preventing apoptosis of T\n                    <jats:sub>reg<\/jats:sub>\n                    cells. PD-L1 is a\n                    <jats:italic>trans<\/jats:italic>\n                    -membrane protein which is recognized as a co-inhibitory factor of immunological responses. Both, PD-1 and PD-L1 function together to downregulate the proliferation of PD-1 positive cells, suppress the expression of cytokines and stimulate apoptosis. Owing to the importance of PD-1\/PD-L1 signaling, this review aims to summarize the potential of PD-1\/PD-L1 inhibitors in CLDs along with toxicities associated with them. We have enlisted some of the important roles of PD-1\/PD-L1 in CLDs, the clinically approved products and the pipelines of drugs under clinical evaluation.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2021.790963","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T12:02:40Z","timestamp":1640260960000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Emerging Role of PD-1\/PD-L1 Inhibitors in Chronic Liver Diseases"],"prefix":"10.3389","volume":"12","author":[{"given":"Vishakha","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prince","family":"Allawadhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil Kumar","family":"Banothu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kala Kumar","family":"Bharani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1182\/blood-2008-12-195792","article-title":"Tumor Antigen-specific CD8 T Cells Infiltrating the Tumor Express High Levels of PD-1 and Are Functionally Impaired","volume":"114","author":"Ahmadzadeh","year":"2009","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"110612","DOI":"10.1016\/j.mehy.2021.110612","article-title":"Decorin as a Possible Strategy for the Amelioration of COVID-19","volume":"152","author":"Allawadhi","year":"2021","journal-title":"Med. Hypotheses"},{"key":"B3","doi-asserted-by":"publisher","first-page":"550","DOI":"10.3389\/fimmu.2016.00550","article-title":"The PD1:PD-L1\/2 Pathway from Discovery to Clinical Implementation","volume":"7","author":"Bardhan","year":"2016","journal-title":"Front. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e1008824","DOI":"10.1080\/2162402X.2015.1008824","article-title":"Interferon-\u03b3-induced Activation of JAK1 and JAK2 Suppresses Tumor Cell Susceptibility to NK Cells through Upregulation of PD-L1 Expression","volume":"4","author":"Bellucci","year":"2015","journal-title":"Oncoimmunology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1200\/jco.2015.33.3_suppl.704","article-title":"Safety and Efficacy of MPDL3280A (Anti-PDL1) in Combination with Bevacizumab (Bev) And\/or FOLFOX in Patients (Pts) with Metastatic Colorectal Cancer (mCRC)","volume":"33","author":"Bendell","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1056\/NEJMoa1504627","article-title":"Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer","volume":"373","author":"Brahmer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.immuni.2007.05.016","article-title":"Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell Responses","volume":"27","author":"Butte","year":"2007","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3567","DOI":"10.1016\/j.molimm.2008.05.014","article-title":"Interaction of Human PD-L1 and B7-1","volume":"45","author":"Butte","year":"2008","journal-title":"Mol. Immunol."},{"key":"B9","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/B978-0-323-44284-8.00017-X","article-title":"Nonneuroendocrine Carcinomas (Excluding Sarcomatoid Carcinoma) and Salivary Gland Analogue Tumors of the Lung","volume-title":"Practical Pulmonary Pathology: A Diagnostic Approach","author":"Cagle","year":"2018"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1002\/hep.28710","article-title":"Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma: Relationship with Clinical and Pathological Features","volume":"64","author":"Calderaro","year":"2016","journal-title":"Hepatology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev.immunol.20.091101.091806","article-title":"The B7 Family of Ligands and its Receptors: New Pathways for Costimulation and Inhibition of Immune Responses","volume":"20","author":"Carreno","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1111\/apm.12703","article-title":"Expression and Prognostic Significance of Programmed Death Protein 1 and Programmed Death Ligand-1, and Cytotoxic T Lymphocyte-Associated Molecule-4 in Hepatocellular Carcinoma","volume":"125","author":"Chang","year":"2017","journal-title":"Apmis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.prp.2016.12.008","article-title":"Tumor-derived CD4+CD25+regulatory T Cells Inhibit Dendritic Cells Function by CTLA-4","volume":"213","author":"Chen","year":"2017","journal-title":"Pathol. Res. Pract."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.3390\/ijms18071517","article-title":"Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis","volume":"18","author":"Cho","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/PPO.0000000000000301","article-title":"PD-L1 and Emerging Biomarkers in Immune Checkpoint Blockade Therapy","volume":"24","author":"Cottrell","year":"2018","journal-title":"Cancer J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1080\/17512433.2017.1389275","article-title":"Atezolizumab in Invasive and Metastatic Urothelial Carcinoma","volume":"10","author":"Crist","year":"2017","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"eaar3593","DOI":"10.1126\/science.aar3593","article-title":"Pan-tumor Genomic Biomarkers for PD-1 Checkpoint Blockade-Based Immunotherapy","volume":"362","author":"Cristescu","year":"2018","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.cellimm.2014.05.006","article-title":"The PD-1\/PD-Ls Pathway and Autoimmune Diseases","volume":"290","author":"Dai","year":"2014","journal-title":"Cell Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.tranon.2017.03.009","article-title":"Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue Is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma","volume":"10","author":"Dai","year":"2017","journal-title":"Transl. Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/jcp.27172","article-title":"PD-1\/PD-L1 Immune Checkpoint: Potential Target for Cancer Therapy","volume":"234","author":"Dermani","year":"2019","journal-title":"J. Cel Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1038\/70932","article-title":"B7-H1, a Third Member of the B7 Family, Co-stimulates T-Cell Proliferation and Interleukin-10 Secretion","volume":"5","author":"Dong","year":"1999","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s12865-019-0309-9","article-title":"CD4+ T Cell Exhaustion Revealed by High PD-1 and LAG-3 Expression and the Loss of Helper T Cell Function in Chronic Hepatitis B","volume":"20","author":"Dong","year":"2019","journal-title":"BMC Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.18632\/oncotarget.13895","article-title":"PD-1 and its Ligands Are Important Immune Checkpoints in Cancer","volume":"8","author":"Dong","year":"2017","journal-title":"Oncotarget"},{"key":"B24","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/eji.201646875","article-title":"Immune Checkpoints and Their Inhibition in Cancer and Infectious Diseases","volume":"47","author":"Dyck","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"LBA101","DOI":"10.1200\/jco.2015.33.15_suppl.lba101","article-title":"Phase I\/II Safety and Antitumor Activity of Nivolumab in Patients with Advanced Hepatocellular Carcinoma (HCC): CA209-040","volume":"33","author":"El-Khoueiry","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e161","DOI":"10.1038\/cti.2017.47","article-title":"Immune Checkpoint Inhibition: Prospects for Prevention and Therapy of Hepatocellular Carcinoma","volume":"6","author":"Elsegood","year":"2017","journal-title":"Clin. Transl. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2967","DOI":"10.1172\/JCI62860","article-title":"Viral Acute Lower Respiratory Infections Impair CD8+ T Cells through PD-1","volume":"122","author":"Erickson","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","article-title":"Engagement of the PD-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation","volume":"192","author":"Freeman","year":"2000","journal-title":"J. Exp. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1158\/1078-0432.CCR-08-1608","article-title":"Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma","volume":"15","author":"Gao","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1016\/j.celrep.2017.04.031","article-title":"Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression","volume":"19","author":"Garcia-Diaz","year":"2017","journal-title":"Cell Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1053\/j.gastro.2009.04.045","article-title":"Profile of Tumor Antigen-specific CD8 T Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma","volume":"137","author":"Gehring","year":"2009","journal-title":"Gastroenterology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40425-018-0316-z","article-title":"Development of PD-1 and PD-L1 Inhibitors as a Form of Cancer Immunotherapy: a Comprehensive Review of Registration Trials and Future Considerations","volume":"6","author":"Gong","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"851","DOI":"10.5858\/arpa.2016-0361-RA","article-title":"Programmed Death Ligand-1 (PD-L1) Expression in the Programmed Death Receptor-1 (PD-1)\/PD-L1 Blockade: a Key Player against Various Cancers","volume":"141","author":"Guan","year":"2017","journal-title":"Arch. Pathol. Lab. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s10147-016-0959-z","article-title":"PD-1\/PD-L1 Blockade in Cancer Treatment: Perspectives and Issues","volume":"21","author":"Hamanishi","year":"2016","journal-title":"Int. J. Clin. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1056\/NEJMoa1305133","article-title":"Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma","volume":"369","author":"Hamid","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B36","first-page":"727","article-title":"PD-1\/PD-L1 Pathway: Current Researches in Cancer","volume":"10","author":"Han","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"451694","DOI":"10.1155\/2011\/451694","article-title":"The PD-1\/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion","volume":"2011","author":"Hofmeyer","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1111\/j.1478-3231.2010.02323.x","article-title":"Increased PD-1 and Decreased CD28 Expression in Chronic Hepatitis B Patients with Advanced Hepatocellular Carcinoma","volume":"30","author":"Hsu","year":"2010","journal-title":"Liver Int."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced Expression of PD-1, a Novel Member of the Immunoglobulin Gene Superfamily, upon Programmed Cell Death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1084\/jem.20022235","article-title":"PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver","volume":"198","author":"Iwai","year":"2003","journal-title":"J. Exp. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12967-014-0373-0","article-title":"PD-1\/PD-L1 Pathway in Non-small-cell Lung Cancer and its Relation with EGFR Mutation","volume":"13","author":"Ji","year":"2015","journal-title":"J. Transl. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"339","DOI":"10.3389\/fimmu.2020.00339","article-title":"Progress and Challenges in Precise Treatment of Tumors with PD-1\/PD-L1 Blockade","volume":"11","author":"Jiang","year":"2020","journal-title":"Front. Immunol."},{"key":"B43","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/82_2010_116","article-title":"Role of PD-1 in Regulating T-Cell Immunity","volume-title":"Negative Co-receptors and Ligands","author":"Jin","year":"2010"},{"key":"B44","doi-asserted-by":"publisher","first-page":"6098","DOI":"10.1158\/1078-0432.CCR-18-3340","article-title":"Correction: Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab","volume":"24","author":"Joseph","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"487","DOI":"10.3389\/fimmu.2020.00487","article-title":"The Role of PD-1 in Acute and Chronic Infection","volume":"11","author":"Jubel","year":"2020","journal-title":"Front. Immunol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"246","DOI":"10.4143\/crt.2016.066","article-title":"Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma","volume":"49","author":"Jung","year":"2017","journal-title":"Cancer Res. Treat."},{"key":"B47","doi-asserted-by":"publisher","first-page":"728","DOI":"10.21037\/atm-20-2948","article-title":"It's All about the Spaces between Cells: Role of Extracellular Matrix in Liver Fibrosis","volume":"9","author":"Khurana","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"789","DOI":"10.3748\/wjg.v25.i7.789","article-title":"Targeted and Immune Therapies for Hepatocellular Carcinoma: Predictions for 2019 and beyond","volume":"25","author":"Kudo","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"149","DOI":"10.2217\/imt-2017-0120","article-title":"PD-1\/PD-L1 in Disease","volume":"10","author":"Kuol","year":"2018","journal-title":"Immunotherapy"},{"key":"B50","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/85330","article-title":"PD-L2 Is a Second Ligand for PD-1 and Inhibits T Cell Activation","volume":"2","author":"Latchman","year":"2001","journal-title":"Nat. Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.3389\/fimmu.2020.01037","article-title":"Anti-PD-1\/PD-L1 Blockade Immunotherapy Employed in Treating Hepatitis B Virus Infection-Related Advanced Hepatocellular Carcinoma: A Literature Review","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"754","DOI":"10.15252\/emmm.201404578","article-title":"ADAP and SKAP55 Deficiency Suppresses PD-1 Expression in CD8+ Cytotoxic T Lymphocytes for Enhanced Anti-tumor Immunotherapy","volume":"7","author":"Li","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1016\/j.jhep.2016.05.032","article-title":"CXCL10\/CXCR3 Signaling Mobilized-Regulatory T Cells Promote Liver Tumor Recurrence after Transplantation","volume":"65","author":"Li","year":"2016","journal-title":"J. Hepatol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.molonc.2015.12.012","article-title":"Essential Role of HDAC6 in the Regulation of PD-L1 in Melanoma","volume":"10","author":"Lienlaf","year":"2016","journal-title":"Mol. Oncol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1002\/cbin.11139","article-title":"JQ1, a BET-Bromodomain Inhibitor, Inhibits Human Cancer Growth and Suppresses PD-L1 Expression","volume":"43","author":"Liu","year":"2019","journal-title":"Cell Biol. Int."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1919082","DOI":"10.1155\/2019\/1919082","article-title":"Beyond T Cells: Understanding the Role of PD-1\/PD-L1 in Tumor-Associated Macrophages","volume":"2019","author":"Lu","year":"2019","journal-title":"J. Immunol. Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.3390\/cancers11101554","article-title":"Predictive Factors for Response to PD-1\/PD-L1 Checkpoint Inhibition in the Field of Hepatocellular Carcinoma: Current Status and Challenges","volume":"11","author":"Macek Jilkova","year":"2019","journal-title":"Cancers"},{"key":"B58","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.clinthera.2015.02.018","article-title":"The Next Immune-Checkpoint Inhibitors: PD-1\/PD-L1 Blockade in Melanoma","volume":"37","author":"Mahoney","year":"2015","journal-title":"Clin. Ther."},{"key":"B59","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1007\/s10147-016-0969-x","article-title":"PD-1\/PD-L1 Blockage in Cancer Treatment-From Basic Research to Clinical Application","volume":"21","author":"Mandai","year":"2016","journal-title":"Int. J. Clin. Oncol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1111\/j.1572-0241.2006.00948.x","article-title":"Expression of PD-1, PD-L1, and PD-L2 in the Liver in Autoimmune Liver Diseases","volume":"102","author":"Mataki","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1093\/annonc\/mdv383","article-title":"Toxicities of the Anti-PD-1 and Anti-PD-L1 Immune Checkpoint Antibodies","volume":"26","author":"Naidoo","year":"2015","journal-title":"Ann. Oncol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.1053\/j.gastro.2008.02.033","article-title":"Functional Restoration of HCV-specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and Compartmentalization","volume":"134","author":"Nakamoto","year":"2008","journal-title":"Gastroenterology"},{"key":"B63","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/hepr.13191","article-title":"Immune Checkpoint Blockade for the Treatment of Human Hepatocellular Carcinoma","volume":"48","author":"Nishida","year":"2018","journal-title":"Hepatol. Res."},{"key":"B64","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1038\/sj.emboj.7601146","article-title":"T-cell Tolerance or Function Is Determined by Combinatorial Costimulatory Signals","volume":"25","author":"Nurieva","year":"2006","journal-title":"Embo J."},{"key":"B65","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.molmed.2014.10.009","article-title":"Human Cancer Immunotherapy with Antibodies to the PD-1 and PD-L1 Pathway","volume":"21","author":"Ohaegbulam","year":"2015","journal-title":"Trends Mol. Med."},{"key":"B66","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.1158\/1078-0432.CCR-04-1469","article-title":"Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer","volume":"11","author":"Ohigashi","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1093\/intimm\/dxm057","article-title":"PD-1 and PD-1 Ligands: from Discovery to Clinical Application","volume":"19","author":"Okazaki","year":"2007","journal-title":"Int. Immunol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"13866","DOI":"10.1073\/pnas.231486598","article-title":"PD-1 Immunoreceptor Inhibits B Cell Receptor-Mediated Signaling by Recruiting Src Homology 2-Domain-Containing Tyrosine Phosphatase 2 to Phosphotyrosine","volume":"98","author":"Okazaki","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B69","doi-asserted-by":"publisher","first-page":"9543","DOI":"10.1128\/MCB.25.21.9543-9553.2005","article-title":"CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms","volume":"25","author":"Parry","year":"2005","journal-title":"Mol. Cel Biol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"ra46","DOI":"10.1126\/scisignal.2002796","article-title":"Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation","volume":"5","author":"Patsoukis","year":"2012","journal-title":"Sci. Signal."},{"key":"B71","doi-asserted-by":"publisher","first-page":"E140","DOI":"10.1002\/lary.28038","article-title":"Pembrolizumab-induced Mucositis in a Patient with Recurrent Hypopharynx Squamous Cell Cancer","volume":"130","author":"Pelster","year":"2020","journal-title":"Laryngoscope"},{"key":"B72","first-page":"76","article-title":"Managing Immune Checkpoint-Blocking Antibody Side Effects","volume-title":"American Society of Clinical Oncology Educational Book","author":"Postow","year":"2015"},{"key":"B73","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1111\/j.1600-6143.2012.04224.x","article-title":"Role of the PD-1 Pathway in the Immune Response","volume":"12","author":"Riella","year":"2012","journal-title":"Am. J. Transpl."},{"key":"B74","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/s41590-018-0044-z","article-title":"The Immunology of Hepatocellular Carcinoma","volume":"19","author":"Ringelhan","year":"2018","journal-title":"Nat. Immunol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1056\/nejmoa1503093","article-title":"Pembrolizumab versus Ipilimumab in Advanced Melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B76","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1530\/ERC-13-0499","article-title":"Endocrine-related Adverse Events Following Ipilimumab in Patients with Advanced Melanoma: a Comprehensive Retrospective Review from a Single Institution","volume":"21","author":"Ryder","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"B77","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.4049\/jimmunol.1701231","article-title":"Dendritic Cell PD-L1 Limits Autoimmunity and Follicular T Cell Differentiation and Function","volume":"200","author":"Sage","year":"2018","journal-title":"J. Immunol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s00251-017-1015-5","article-title":"PD-1 and Cancer: Molecular Mechanisms and Polymorphisms","volume":"70","author":"Salmaninejad","year":"2018","journal-title":"Immunogenetics"},{"key":"B79","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1097\/PPO.0000000000000061","article-title":"Inducible Expression of B7-H1 (PD-L1) and its Selective Role in Tumor Site Immune Modulation","volume":"20","author":"Sanmamed","year":"2014","journal-title":"Cancer J."},{"key":"B80","doi-asserted-by":"publisher","first-page":"207","DOI":"10.3389\/fcimb.2019.00207","article-title":"The PD-1\/PD-L1 Axis and Virus Infections: A Delicate Balance","volume":"9","author":"Sch\u00f6nrich","year":"2019","journal-title":"Front. Cel Infect. Microbiol."},{"key":"B81","doi-asserted-by":"publisher","first-page":"3637","DOI":"10.4049\/jimmunol.170.7.3637","article-title":"B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy","volume":"170","author":"Selenko-Gebauer","year":"2003","journal-title":"J. Immunol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/ni1443","article-title":"The Function of Programmed Cell Death 1 and its Ligands in Regulating Autoimmunity and Infection","volume":"8","author":"Sharpe","year":"2007","journal-title":"Nat. Immunol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.febslet.2004.07.083","article-title":"PD-1 Inhibits T-Cell Receptor Induced Phosphorylation of the ZAP70\/CD3zeta Signalosome and Downstream Signaling to PKCtheta","volume":"574","author":"Sheppard","year":"2004","journal-title":"FEBS Lett."},{"key":"B84","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/ijc.25397","article-title":"PD-1 and PD-L1 Upregulation Promotes CD8(+) T-Cell Apoptosis and Postoperative Recurrence in Hepatocellular Carcinoma Patients","volume":"128","author":"Shi","year":"2011","journal-title":"Int. J. Cancer"},{"key":"B85","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3389\/fonc.2018.00269","article-title":"Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma","volume":"8","author":"Shrestha","year":"2018","journal-title":"Front. Oncol."},{"key":"B86","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/B978-0-12-821567-8.00008-7","article-title":"Glioblastoma Cell-Induced Immunosuppression Causing Chemoresistance","volume-title":"Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies","author":"Sordillo","year":"2021"},{"key":"B87","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.immuni.2014.10.013","article-title":"The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8(+) T Cells during Chronic Infection","volume":"41","author":"Staron","year":"2014","journal-title":"Immunity"},{"key":"B88","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.immuni.2018.03.014","article-title":"Regulation and Function of the PD-L1 Checkpoint","volume":"48","author":"Sun","year":"2018","journal-title":"Immunity"},{"key":"B89","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/B978-0-12-803741-6.00014-8","article-title":"Novel Therapies for Advanced Cervical Cancer","volume-title":"Translational Advances in Gynecologic Cancers","author":"Tewari","year":"2017"},{"key":"B90","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.4049\/jimmunol.1402180","article-title":"Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism","volume":"194","author":"Tkachev","year":"2015","journal-title":"J. Immunol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune Checkpoint Blockade: a Common Denominator Approach to Cancer Therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B92","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/B978-0-12-821909-6.00003-1","article-title":"YY1 Expression and PD-1 Regulation in CD8 T Lymphocytes","volume-title":"YY1 in the Control of the Pathogenesis and Drug Resistance of Cancer","author":"Touboul","year":"2021"},{"key":"B93","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.jhep.2007.12.014","article-title":"Restoration of HCV-specific T Cell Functions by PD-1\/PD-L1 Blockade in HCV Infection: Effect of Viremia Levels and Antiviral Treatment","volume":"48","author":"Urbani","year":"2008","journal-title":"J. Hepatol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.3748\/wjg.v17.i28.3322","article-title":"Immunostaining of PD-1\/PD-Ls in Liver Tissues of Patients with Hepatitis and Hepatocellular Carcinoma","volume":"17","author":"Wang","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1097\/PPO.0000000000000296","article-title":"Toxicities Associated with PD-1\/PD-L1 Blockade","volume":"24","author":"Wang","year":"2018","journal-title":"Cancer J."},{"key":"B96","doi-asserted-by":"publisher","first-page":"536","DOI":"10.3389\/fphar.2018.00536","article-title":"Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1111\/j.1365-2893.2010.01313.x","article-title":"PD-1\/PD-L1 Pathway and T-Cell Exhaustion in Chronic Hepatitis Virus Infection","volume":"17","author":"Watanabe","year":"2010","journal-title":"J. Viral Hepat."},{"key":"B98","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1200\/JCO.2014.60.0379","article-title":"Toxicities of Immunotherapy for the Practitioner","volume":"33","author":"Weber","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"9018","DOI":"10.1200\/jco.2015.33.15_suppl.9018","article-title":"Safety Profile of Nivolumab (NIVO) in Patients (Pts) with Advanced Melanoma (MEL): a Pooled Analysis","volume":"33","author":"Weber","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"B100","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab Plus Ipilimumab in Advanced Melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B101","doi-asserted-by":"publisher","first-page":"8067","DOI":"10.1158\/0008-5472.CAN-09-0901","article-title":"Kupffer Cell Suppression of CD8+ T Cells in Human Hepatocellular Carcinoma Is Mediated by B7-H1\/programmed Death-1 Interactions","volume":"69","author":"Wu","year":"2009","journal-title":"Cancer Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"15419","DOI":"10.1073\/pnas.1206370109","article-title":"Activator Protein 1 Suppresses Antitumor T-Cell Function via the Induction of Programmed Death 1","volume":"109","author":"Xiao","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B103","doi-asserted-by":"publisher","first-page":"e1356144","DOI":"10.1080\/2162402X.2017.1356144","article-title":"Analysis of PD1, PDL1, PDL2 Expression and T Cells Infiltration in 1014 Gastric Cancer Patients","volume":"7","author":"Xing","year":"2018","journal-title":"Oncoimmunology"},{"key":"B104","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.3389\/fimmu.2017.01597","article-title":"PD-1\/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?","volume":"8","author":"Xu-Monette","year":"2017","journal-title":"Front. Immunol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"5538","DOI":"10.4049\/jimmunol.169.10.5538","article-title":"Expression of Programmed Death 1 Ligands by Murine T Cells and APC","volume":"169","author":"Yamazaki","year":"2002","journal-title":"J. Immunol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1089\/vim.2006.0096","article-title":"T Cell Dysfunction by Hepatitis C Virus Core Protein Involves PD-1\/PDL-1 Signaling","volume":"20","author":"Yao","year":"2007","journal-title":"Viral Immunol."},{"key":"B107","doi-asserted-by":"publisher","first-page":"3158","DOI":"10.1158\/1078-0432.CCR-16-1761","article-title":"PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer","volume":"23","author":"Yearley","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"B108","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.immuni.2011.06.015","article-title":"Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-specific CD8(+) T Cells","volume":"35","author":"Youngblood","year":"2011","journal-title":"Immunity"},{"key":"B109","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.1016\/j.str.2015.09.010","article-title":"Structure of the Complex of Human Programmed Death 1, PD-1, and its Ligand PD-L1","volume":"23","author":"Zak","year":"2015","journal-title":"Structure"},{"key":"B110","doi-asserted-by":"publisher","first-page":"1758835920937612","DOI":"10.1177\/1758835920937612","article-title":"Efficacy of PD-1\/PD-L1 Blockade Monotherapy in Clinical Trials","volume":"12","author":"Zhao","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"651","DOI":"10.2217\/imt-2018-0214","article-title":"Efficacy and Safety of Nivolumab Plus Apatinib in Advanced Liver Carcinosarcoma: a Case Report","volume":"11","author":"Zhao","year":"2019","journal-title":"Immunotherapy"},{"key":"B112","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4137\/BIC.S29325","article-title":"Human Cancer Immunotherapy with PD-1\/PD-L1 Blockade","volume":"7","author":"Zheng","year":"2015","journal-title":"Biomark Cancer"},{"key":"B113","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1002\/eji.200737461","article-title":"PD-L2 Expression Extends beyond Dendritic Cells\/macrophages to B1 Cells Enriched for V(H)11\/V(H)12 and Phosphatidylcholine Binding","volume":"37","author":"Zhong","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.immuni.2018.12.024","article-title":"Liver-resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD-1-PD-L1 axis","volume":"50","author":"Zhou","year":"2019","journal-title":"Immunity"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.790963\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T12:02:53Z","timestamp":1640260973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.790963\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,23]]},"references-count":114,"alternative-id":["10.3389\/fphar.2021.790963"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.790963","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,23]]},"article-number":"790963"}}