Spatiotemporal Changes in Checkpoint Molecule Expression

  • Wenhua LiEmail author
  • Jingbo Qie
  • Yao Zhang
  • Jinjia Chang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1248)


Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have led to therapeutic breakthrough in patients with advanced malignancy, covering the lung, breast, gastrointestinal, head and neck, urinary system, lymphoma, and solid tumor harboring MSI/dMMR. In certain cancer types, the expression level of immune checkpoint molecule will be required if the immune-based approaches are considered, especially the PD-L1 expression. However, in other types, survival benefit has been proven regardless of PD-L1 expression. It raises a question of how to select patients for immune therapy and whether the expression of immune checkpoint molecules will be optimal biomarkers. Before answering this question, a comprehensive map for the expression of immune checkpoint molecules is needed. In this chapter, we describe our current knowledge on the spatiotemporal changes in the expression of checkpoint molecules. We discuss the different frequencies of expression depending on tumor types and stages, the different patterns between primary and metastatic tumors, as well as the change of expression before and after treatment. The expression of PD-L1 has been most studied, but the threshold that separate “positive” and “negative” PD-L1 expressions and the consistency of testing platform remain under debate. Better understanding on the tumor microenvironment and expression of checkpoint molecules will help to identify patients who will benefit from checkpoint blockade therapy.


Immune checkpoint molecule Spatiotemporal change Malignancy Immunotherapy 


  1. Ali HR, Glont SE, Blows FM et al (2015) PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol: Off J Eur Soc Med Oncol 26(7):1488–1493CrossRefGoogle Scholar
  2. Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319CrossRefGoogle Scholar
  3. Antonia SJ, López-Martin JA, Bendell J et al (2016) Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17(7):883–895CrossRefGoogle Scholar
  4. Arigami T, Narita N, Mizuno R et al (2010) B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis. Ann Surg 252(6):1044–1051CrossRefGoogle Scholar
  5. Balar AV, Castellano D, O’Donnell PH et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18(11):1483–1492CrossRefGoogle Scholar
  6. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J (2016) Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 47(1):78–84CrossRefGoogle Scholar
  7. Baruah P, Bullenkamp J, Wilson POG, Lee M, Kaski JC, Dumitriu IE (2019) TLR9 mediated tumor-stroma interactions in Human Papilloma Virus (HPV)-positive head and neck squamous Cell carcinoma Up-regulate PD-L1 and PD-L2. Front Immunol 10:1644CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bauml J, Seiwert TY, Pfister DG et al (2016) Preliminary results from KEYNOTE-055: pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 34(15_suppl):6011Google Scholar
  9. Bedekovics J, Beke L, Mokanszki A, Szilagyi S, Mehes G (2018) Programmed death-ligand 1 (PD-L1) expression in thymic epithelial tumors. Appl Immunohistochem Mol MorpholGoogle Scholar
  10. Bellmunt J, Mullane SA, Werner L et al (2015) Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol 26(4):812–817CrossRefGoogle Scholar
  11. Bellmunt J, de Wit R, Vaughn DJ et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bin Z, Guangbo Z, Yan G, Huan Z, Desheng L, Xueguang Z (2014) Overexpression of B7-H3 in CD133 + colorectal cancer cells is associated with cancer progression and survival in human patients. J Surg Res 188(2):396–403CrossRefGoogle Scholar
  13. Boger C, Behrens HM, Kruger S, Rocken C (2017) The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: A future perspective for a combined gastric cancer therapy? Oncoimmunology 6(4):e1293215CrossRefPubMedPubMedCentralGoogle Scholar
  14. Boorjian SA, Sheinin Y, Crispen PL et al (2008) T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res 14(15):4800–4808CrossRefGoogle Scholar
  15. Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639CrossRefPubMedPubMedCentralGoogle Scholar
  16. Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135CrossRefPubMedPubMedCentralGoogle Scholar
  17. Brown H, Vansteenkiste J, Nakagawa K et al (2019) Brief report: programmed cell death ligand 1 expression in untreated EGFR mutated advanced non-small cell lung cancer and response to osimertinib versus comparator in FLAURA. J Thorac OncolGoogle Scholar
  18. Burugu S, Gao D, Leung S, Chia SK, Nielsen TO (2018) TIM-3 expression in breast cancer. Oncoimmunology 7(11):e1502128CrossRefPubMedPubMedCentralGoogle Scholar
  19. Callea M, Albiges L, Gupta M et al (2015) Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 3(10):1158–1164CrossRefPubMedPubMedCentralGoogle Scholar
  20. Camisaschi C, De Filippo A, Beretta V et al (2014) Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol 134(7):1893–1902CrossRefGoogle Scholar
  21. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202-209Google Scholar
  22. Cappello P, Triebel F, Iezzi M et al (2003) LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. Can Res 63(10):2518–2525Google Scholar
  23. Carbone DP, Reck M, Paz-Ares L et al (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376(25):2415–2426CrossRefPubMedPubMedCentralGoogle Scholar
  24. Chen BJ, Chapuy B, Ouyang J et al (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res: Off J Am Assoc Cancer Res 19(13):3462–3473CrossRefGoogle Scholar
  25. Cheng G, Li M, Wu J et al (2015) Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis. Int J Clin Exp Pathol 8(8):9452–9457PubMedPubMedCentralGoogle Scholar
  26. Chung HC, Ros W, Delord JP et al (2019) Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol: Off J Am Soc Clin Oncol 37(17):1470–1478CrossRefGoogle Scholar
  27. Cong F, Yu H, Gao X (2017) Expression of CD24 and B7-H3 in breast cancer and the clinical significance. Oncol Lett 14(6):7185–7190PubMedPubMedCentralGoogle Scholar
  28. Cooper WA, Tran T, Vilain RE et al (2015) PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma. Lung Cancer 89(2):181–188CrossRefGoogle Scholar
  29. D’Angelo SP, Shoushtari AN, Agaram NP et al (2015) Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 46(3):357–365CrossRefGoogle Scholar
  30. Dail M, Yang L, Green C et al (2016) Distinct patterns of PD-L1 and PD-L2 expression by tumor and non-tumor cells in patients with MM, MDS and AML. Blood 128(22):1340Google Scholar
  31. Danilova L, Wang H, Sunshine J et al (2016) Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors. Proc Natl Acad Sci USA 113(48):E7769–E7777CrossRefGoogle Scholar
  32. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE (1950) Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol (Baltimore, Md: 1950) 176(5):3000–3009Google Scholar
  33. Deng L, Gyorffy B, Na F et al (2015) Association of PDCD1 and CTLA-4 gene expression with clinicopathological factors and survival in non-small-cell lung cancer: results from a large and pooled microarray database. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer 10(7):1020–1026CrossRefGoogle Scholar
  34. Derks S, Nason KS, Liao X et al (2015) Epithelial PD-L2 expression marks Barrett’s esophagus and esophageal adenocarcinoma. Cancer Immunol Res 3(10):1123–1129CrossRefPubMedPubMedCentralGoogle Scholar
  35. Dietel M, Savelov N, Salanova R et al (2018) 130O Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): the global, multicentre EXPRESS study. J Thorac Oncol 13(4):S74–S75CrossRefGoogle Scholar
  36. Dill EA, Gru AA, Atkins KA et al (2017) PD-L1 expression and intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol 41(3):334–342CrossRefGoogle Scholar
  37. Doi T, Piha-Paul SA, Jalal SI et al (2018) Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol 36(1):61–67Google Scholar
  38. Doroshow DB, Sanmamed MF, Hastings K et al (2019) Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res: Off J Am Assoc Cancer ResGoogle Scholar
  39. Droeser RA, Hirt C, Viehl CT et al (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49(9):2233–2242CrossRefGoogle Scholar
  40. El-Khoueiry AB, Sangro B, Yau T et al (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (London, England) 389(10088):2492–2502CrossRefGoogle Scholar
  41. Emens LA, Cruz C, Eder JP et al (2019) Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 studyatezolizumab therapy for patients with metastatic triple-negative breast canceratezolizumab therapy for patients with metastatic triple-negative breast cancer. JAMA Oncol 5(1):74–82CrossRefGoogle Scholar
  42. Enwere EK, Kornaga EN, Dean M et al (2017) Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer. Mod Pathol: Off J U S Can Acad Pathol, Inc 30(4):577–586Google Scholar
  43. Ferris RL, Blumenschein G Jr, Fayette J et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867CrossRefPubMedPubMedCentralGoogle Scholar
  44. Frenel JS, Le Tourneau C, O’Neil B et al (2017) Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol: Off J Am Soc Clin Oncol 35(36):4035–4041CrossRefGoogle Scholar
  45. Fuchs CS, Doi T, Jang RW et al (2018) Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 4(5):e180013CrossRefPubMedPubMedCentralGoogle Scholar
  46. Fujimoto D, Uehara K, Sato Y et al (2017) Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients. Sci Rep 7(1):11373CrossRefPubMedPubMedCentralGoogle Scholar
  47. Gandhi MK, Lambley E, Duraiswamy J et al (2006) Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8 + T-cell function in Hodgkin lymphoma patients. Blood 108(7):2280–2289CrossRefGoogle Scholar
  48. Gao Q, Wang XY, Qiu SJ et al (2009) Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res 15(3):971–979CrossRefGoogle Scholar
  49. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 372(21):2018–2028CrossRefGoogle Scholar
  50. Gettinger SN, Horn L, Gandhi L et al (2015) Overall survival and long-term safety of nivolumab (Anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously Treated advanced non-small-cell lung cancer. J Clin Oncol: Off J Am Soc Clin Oncol 33(18):2004–2012CrossRefGoogle Scholar
  51. Giaccone G, Kim C, Thompson J et al (2018) Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 19(3):347–355CrossRefGoogle Scholar
  52. Grosso JF, Kelleher CC, Harris TJ et al (2007) LAG-3 regulates CD8 + T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Investig 117(11):3383–3392CrossRefGoogle Scholar
  53. Guo PD, Sun ZW, Lai HJ et al (2018) Clinicopathological analysis of PD-L2 expression in colorectal cancer. OncoTargets Ther 11:7635–7642CrossRefGoogle Scholar
  54. Hamanishi J, Mandai M, Iwasaki M et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8 + T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365CrossRefGoogle Scholar
  55. Hamid O, Puzanov I, Dummer R et al (2017) Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer 86:37–45CrossRefGoogle Scholar
  56. Han L, Liu F, Li R et al (2014) Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma. Oncol Lett 8(4):1461–1469CrossRefPubMedPubMedCentralGoogle Scholar
  57. Han JJ, Kim DW, Koh J et al (2016) Change in PD-L1 expression after acquiring resistance to gefitinib in EGFR-mutant non-small-cell lung cancer. Clin Lung Cancer 17(4):263–270 e2Google Scholar
  58. Haratake N, Toyokawa G, Tagawa T et al (2017) Positive conversion of PD-L1 expression after treatments with chemotherapy and nivolumab. Anticancer Res 37(10):5713–5717PubMedGoogle Scholar
  59. Hashizume A, Umemoto S, Yokose T et al (2018) Enhanced expression of PD-L1 in non-muscle-invasive bladder cancer after treatment with Bacillus calmette-guerin. Oncotarget 9(75):34066–34078CrossRefPubMedPubMedCentralGoogle Scholar
  60. He Y, Yu H, Rozeboom L et al (2017) LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer 12(5):814–823CrossRefGoogle Scholar
  61. Heeren AM, van Dijk I, Berry D et al (2018) Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer. Front Immunol 9:1598CrossRefPubMedPubMedCentralGoogle Scholar
  62. Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (London, England) 387(10027):1540–1550CrossRefGoogle Scholar
  63. Herbst RS, Baas P, Perez-Gracia JL et al (2019) Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Ann Oncol: Off J Eur Soc Med Oncol 30(2):281–289CrossRefGoogle Scholar
  64. Hersom M, Jorgensen JT (2018) Companion and complementary diagnostics-focus on PD-L1 expression assays for PD-1/PD-L1 checkpoint inhibitors in non-small cell lung cancer. Ther Drug Monit 40(1):9–16PubMedGoogle Scholar
  65. Horn L, Mansfield AS, Szczesna A et al (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379(23):2220–2229CrossRefGoogle Scholar
  66. Hsieh C-C, Hsu H-S, Li AF-Y, Chen Y-J (2018) Clinical relevance of PD-L1 and PD-L2 overexpression in patients with esophageal squamous cell carcinoma. J Thorac Dis 10(7):4433–4444Google Scholar
  67. Hu Y, Lv X, Wu Y et al (2015) Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia. Hematology (Amsterdam, Netherlands) 20(4):187–195Google Scholar
  68. Ilie M, Long-Mira E, Bence C et al (2016) Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol: Off J Eur Soc Med Oncol 27(1):147–153CrossRefGoogle Scholar
  69. Ingebrigtsen VA, Boye K, Tekle C, Nesland JM, Flatmark K, Fodstad O (2012) B7-H3 expression in colorectal cancer: nuclear localization strongly predicts poor outcome in colon cancer. Int J Cancer 131(11):2528–2536CrossRefGoogle Scholar
  70. Ingebrigtsen VA, Boye K, Nesland JM, Nesbakken A, Flatmark K, Fodstad O (2014) B7-H3 expression in colorectal cancer: associations with clinicopathological parameters and patient outcome. BMC Cancer 14:602CrossRefPubMedPubMedCentralGoogle Scholar
  71. Inoue Y, Yoshimura K, Kurabe N et al (2017) Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer. Oncotarget 8(5):8738–8751CrossRefPubMedPubMedCentralGoogle Scholar
  72. Ise W, Kohyama M, Nutsch KM et al (2010) CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 11(2):129–135CrossRefGoogle Scholar
  73. Ishii H, Azuma K, Kawahara A et al (2015) Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer 10(3):426–430CrossRefGoogle Scholar
  74. Janjigian YY, Bendell J, Calvo E et al (2018) CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol: Off J Am Soc Clin Oncol 36(28):2836–2844CrossRefGoogle Scholar
  75. Jia Y, Wang H, Wang Y et al (2015) Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer 137(5):1095–1106CrossRefGoogle Scholar
  76. Jung HI, Jeong D, Ji S et al (2017) Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat: Off J Korean Cancer Assoc 49(1):246–254CrossRefGoogle Scholar
  77. Kakavand H, Jackett LA, Menzies AM et al (2017) Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol: Off J U S Can Acad Pathol, Inc 30(12):1666–1676Google Scholar
  78. Kang YK, Boku N, Satoh T et al (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 390(10111):2461–2471CrossRefGoogle Scholar
  79. Katsuya Y, Fujita Y, Horinouchi H, Ohe Y, Watanabe S, Tsuta K (2015) Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 88(2):154–159CrossRefGoogle Scholar
  80. Katsuya Y, Horinouchi H, Asao T et al (2016) Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: impact on treatment efficacy and alteration in expression after chemotherapy. Lung Cancer 99:4–10CrossRefGoogle Scholar
  81. Kaufman KA, Bowen JA, Tsai AF, Bluestone JA, Hunt JS, Ober C (1999) The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod 5(1):84–87CrossRefGoogle Scholar
  82. Kawazoe A, Kuwata T, Kuboki Y et al (2017) Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer: Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc 20(3):407–415CrossRefGoogle Scholar
  83. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol 26:677–704CrossRefGoogle Scholar
  84. Kim SS, Kim SH, Kang HS et al (2010) Molecular cloning and expression analysis of pig lymphocyte activation gene-3 (LAG-3; CD223). Vet Immunol Immunopathol 133(1):72–79CrossRefGoogle Scholar
  85. Kim JR, Moon YJ, Kwon KS et al (2013) Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS ONE 8(12):e82870CrossRefPubMedPubMedCentralGoogle Scholar
  86. Kim S, Koh J, Kwon D et al (2017) Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur J Cancer 75:141–149CrossRefGoogle Scholar
  87. Kitazono S, Fujiwara Y, Tsuta K et al (2015) Reliability of small biopsy samples compared with resected specimens for the determination of programmed death-ligand 1 expression in non–small-cell lung cancer. Clin Lung Cancer 16(5):385–390CrossRefGoogle Scholar
  88. Kotaskova J, Tichy B, Trbusek M et al (2010) High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J Mol Diagn: JMD 12(3):328–334CrossRefGoogle Scholar
  89. Kudo T, Hamamoto Y, Kato K et al (2017) Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 18(5):631–639CrossRefGoogle Scholar
  90. Kulangara KHD, Waldroup S et al (2017) Development of the combined positive score for the evaluation of PD-L1 in solid tumors with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx. J Clin Oncol 35S:ASCO#e14589Google Scholar
  91. Latchman Y, Wood CR, Chernova T et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268CrossRefGoogle Scholar
  92. Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520CrossRefPubMedPubMedCentralGoogle Scholar
  93. Lee LH, Cavalcanti MS, Segal NH et al (2016) Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 29:1433CrossRefPubMedPubMedCentralGoogle Scholar
  94. Lee J, Park CK, Yoon HK et al (2019) PD-L1 expression in ROS1-rearranged non-small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1. Thoracic cancer 10(1):103–110CrossRefGoogle Scholar
  95. Li F, Zhao Y, Wei L, Li S, Liu J (2018) Tumor-infiltrating Treg, MDSC, and IDO expression associated with outcomes of neoadjuvant chemotherapy of breast cancer. Cancer Biol Ther 19(8):695–705CrossRefPubMedPubMedCentralGoogle Scholar
  96. Liao H, Chen W, Dai Y et al (2019) Expression of programmed cell death-ligands in hepatocellular carcinoma: correlation with immune microenvironment and survival outcomes. Front Oncol 9:883CrossRefPubMedPubMedCentralGoogle Scholar
  97. Llosa NJ, Cruise M, Tam A et al (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5(1):43–51CrossRefPubMedPubMedCentralGoogle Scholar
  98. Lou Y, Diao L, Cuentas ER et al (2016) Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res 22(14):3630–3642CrossRefGoogle Scholar
  99. Ma W, Duan H, Zhang R et al (2019) High expression of indoleamine 2, 3-dioxygenase in adenosquamous lung carcinoma correlates with favorable patient outcome. J Cancer 10(1):267–276CrossRefPubMedPubMedCentralGoogle Scholar
  100. Madore J, Vilain RE, Menzies AM et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28(3):245–253CrossRefGoogle Scholar
  101. Manson QF, Schrijver W, Ter Hoeve ND, Moelans CB, van Diest PJ (2019) Frequent discordance in PD-1 and PD-L1 expression between primary breast tumors and their matched distant metastases. Clin Exp Metas 36(1):29–37CrossRefGoogle Scholar
  102. Masugi Y, Nishihara R, Yang J et al (2017) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut 66(8):1463–1473CrossRefGoogle Scholar
  103. Mehra R, Seiwert TY, Gupta S et al (2018) Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119(2):153–159CrossRefPubMedPubMedCentralGoogle Scholar
  104. Mezache L, Paniccia B, Nyinawabera A, Nuovo GJ (2015) Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod Pathol: Off J U S Can Acad Pathol, Inc 28(12):1594–1602Google Scholar
  105. Mittendorf EA, Philips AV, Meric-Bernstam F et al (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370CrossRefPubMedPubMedCentralGoogle Scholar
  106. Motzer RJ, Rini BI, McDermott DF et al (2015a) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol: Off J Am Soc Clin Oncol 33(13):1430–1437CrossRefGoogle Scholar
  107. Motzer RJ, Escudier B, McDermott DF et al (2015b) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813CrossRefPubMedPubMedCentralGoogle Scholar
  108. Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290CrossRefPubMedPubMedCentralGoogle Scholar
  109. Muro K, Chung HC, Shankaran V et al (2016) Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 17(6):717–726CrossRefGoogle Scholar
  110. Nagaraju K, Raben N, Villalba ML et al (1999) Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells. Clin Immunol (Orlando, Fla) 92(2):161–169CrossRefGoogle Scholar
  111. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S (2007) Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol, Immunother: CII 56(8):1173–1182CrossRefGoogle Scholar
  112. Nomi T, Sho M, Akahori T et al (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 13(7):2151–2157CrossRefGoogle Scholar
  113. Obeid JM, Erdag G, Smolkin ME et al (2016) PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 5(11):e1235107CrossRefPubMedPubMedCentralGoogle Scholar
  114. Ogawa M, Watanabe M, Hasegawa T, Ichihara K, Yoshida K, Yanaga K (2017) Expression of CXCR-4 and IDO in human colorectal cancer: an immunohistochemical approach. Mol Clin Oncol 6(5):701–704CrossRefPubMedPubMedCentralGoogle Scholar
  115. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X (2015) Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 21(1):24–33CrossRefGoogle Scholar
  116. O’Malley D, Sudarsanam S, Chizhevsky V et al (2017) BRAF mutation and PD-L1 expression in melanoma: Comparison between multiple PD-L1 IHC clones and BRAF mutation evalutated by FDA-approved kits versus NGS. J Clin Oncol 35(15_suppl):e21050-eGoogle Scholar
  117. Ott PA, Fernandez MEE, Hiret S et al (2015) Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol 33(15_suppl):7502Google Scholar
  118. Overman MJ, McDermott R, Leach JL et al (2017) 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 18(9):1182–1191CrossRefPubMedPubMedCentralGoogle Scholar
  119. Overman MJ, Lonardi S, Wong KYM et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol: Off J Am Soc Clin Oncol 36(8):773–779CrossRefGoogle Scholar
  120. Panjwani PK, Charu V, DeLisser M, Molina-Kirsch H, Natkunam Y, Zhao S (2018) Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol 71:91–99CrossRefGoogle Scholar
  121. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefPubMedPubMedCentralGoogle Scholar
  122. Paulsen EE, Kilvaer TK, Rakaee M et al (2017) CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases. Cancer Immunol, Immunother: CII 66(11):1449–1461CrossRefGoogle Scholar
  123. Petrylak DP, Powles T, Bellmunt J et al (2018) Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: long-term outcomes from a phase 1 study. JAMA Oncol 4(4):537–544CrossRefPubMedPubMedCentralGoogle Scholar
  124. Pinato DJ, Shiner RJ, White SD et al (2016) Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy. Oncoimmunology 5(9):e1213934CrossRefPubMedPubMedCentralGoogle Scholar
  125. Reck M, Rodriguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833CrossRefGoogle Scholar
  126. Rehman JA, Han G, Carvajal-Hausdorf DE et al (2017) Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Mod Pathol: Off J U S Can Acad Pathol, Inc 30(3):340–349Google Scholar
  127. Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918CrossRefGoogle Scholar
  128. Rijnders M, van der Veldt AAM, Zuiverloon TCM et al (2019) PD-L1 antibody comparison in urothelial carcinoma. Eur Urol 75(3):538–540CrossRefGoogle Scholar
  129. Rizvi NA, Mazieres J, Planchard D et al (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265CrossRefPubMedPubMedCentralGoogle Scholar
  130. Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330CrossRefPubMedPubMedCentralGoogle Scholar
  131. Rodić N, Anders RA, Eshleman JR et al (2015) PD-L1 expression in melanocytic lesions does not correlate with the BRAF V600E mutation. Cancer Immunol Res 3(2):110–115CrossRefGoogle Scholar
  132. Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England) 387(10031):1909–1920CrossRefGoogle Scholar
  133. Schachter J, Ribas A, Long GV et al (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet (London, England) 390(10105):1853–1862CrossRefGoogle Scholar
  134. Schmid P, Adams S, Rugo HS et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379(22):2108–2121CrossRefPubMedPubMedCentralGoogle Scholar
  135. Schultheis AM, Scheel AH, Ozretic L et al (2015) PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 51(3):421–426CrossRefGoogle Scholar
  136. Sequist LV, Chiang A, Gilbert J et al (2016) Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Ann Oncol 27(suppl_6)Google Scholar
  137. Shah MA, Kojima T, Hochhauser D et al (2018) Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA OncolGoogle Scholar
  138. Sharma P, Callahan MK, Bono P et al (2016) Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17(11):1590–1598CrossRefPubMedPubMedCentralGoogle Scholar
  139. Shin SJ, Jeon YK, Kim PJ et al (2016) Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 23(2):694–702CrossRefGoogle Scholar
  140. Silva R, Gullo I, Carneiro F (2016) The PD-1:PD-L1 immune inhibitory checkpoint in Helicobacter pylori infection and gastric cancer: a comprehensive review and future perspectives. Porto Biomed J 1(1):4–11CrossRefGoogle Scholar
  141. Snyder A, Makarov V, Merghoub T et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199CrossRefPubMedPubMedCentralGoogle Scholar
  142. Spira AI, Park K, Mazières J et al (2015) Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A versus docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol 33(15_suppl):8010Google Scholar
  143. Sun J, Xu K, Wu C et al (2007) PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies. Tissue Antigens 69(1):19–27CrossRefGoogle Scholar
  144. Takaya S, Saito H, Ikeguchi M (2015) Upregulation of immune checkpoint molecules, PD-1 and LAG-3, on CD4 + and CD8 + T cells after gastric cancer surgery. Yonago Acta Med 58(1):39–44PubMedPubMedCentralGoogle Scholar
  145. Tanaka K, Miyata H, Sugimura K et al (2016) Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy. Cancer Sci 107(6):726–733CrossRefPubMedPubMedCentralGoogle Scholar
  146. Tanaka Y, Maeshima AM, Nomoto J et al (2018) Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol 100(5):511–517CrossRefGoogle Scholar
  147. Tanegashima T, Togashi Y, Azuma K et al (2019) Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. Clin Cancer Res: Off J Am Assoc Cancer Res 2019Google Scholar
  148. Taube JM, Anders RA, Young GD et al (2012) Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4(127):127ra37-12ra37Google Scholar
  149. Tessier-Cloutier B, Kalloger SE, Al-Kandari M et al (2017) Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma. BMC Cancer 17(1):618CrossRefPubMedPubMedCentralGoogle Scholar
  150. Thiem A, Hesbacher S, Kneitz H et al (2019) IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression. J Exp Clin Cancer Res 38(1):397CrossRefPubMedPubMedCentralGoogle Scholar
  151. Thompson RH, Kuntz SM, Leibovich BC et al (2006) Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Can Res 66(7):3381–3385CrossRefGoogle Scholar
  152. Triebel F, Jitsukawa S, Baixeras E et al (1990) LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 171(5):1393–1405CrossRefGoogle Scholar
  153. Vilain RE, Menzies AM, Wilmott JS et al (2017) Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res: Off J Am Assoc Cancer Res 23(17):5024–5033CrossRefGoogle Scholar
  154. Villarroel-Espindola F, Yu X, Datar I et al (2018) Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 24(7):1562–1573CrossRefGoogle Scholar
  155. Wainwright DA, Balyasnikova IV, Chang AL et al (2012) IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res: Off J Am Assoc Cancer Res 18(22):6110–6121CrossRefGoogle Scholar
  156. Wang XB, Giscombe R, Yan Z, Heiden T, Xu D, Lefvert AK (2002) Expression of CTLA-4 by human monocytes. Scand J Immunol 55(1):53–60CrossRefGoogle Scholar
  157. Wang J, Chong KK, Nakamura Y et al (2013) B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. J Invest Dermatol 133(8):2050–2058CrossRefPubMedPubMedCentralGoogle Scholar
  158. Wang K, Yuen ST, Xu J et al (2014) Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46(6):573–582CrossRefGoogle Scholar
  159. Wang HB, Yao H, Li CS et al (2017a) Rise of PD-L1 expression during metastasis of colorectal cancer: Implications for immunotherapy. J Dig Dis 18(10):574–581CrossRefGoogle Scholar
  160. Wang H, Yao H, Li C et al (2017) PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation. Oncoimmunology 6(7):e1327494-eGoogle Scholar
  161. Wang Y, Dong T, Xuan Q, Zhao H, Qin L, Zhang Q (2018) Lymphocyte-activation gene-3 expression and prognostic value in neoadjuvant-treated triple-negative breast cancer. J Breast Cancer 21(2):124–133CrossRefPubMedPubMedCentralGoogle Scholar
  162. Wang X, Zhang T, Song Z et al (2019) Tumor CD73/A2aR adenosine immunosuppressive axis and tumor-infiltrating lymphocytes in diffuse large B-cell lymphoma: correlations with clinicopathological characteristics and clinical outcome. Int J CancerGoogle Scholar
  163. Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384CrossRefGoogle Scholar
  164. Weissferdt A, Fujimoto J, Kalhor N et al (2017) Expression of PD-1 and PD-L1 in thymic epithelial neoplasms. Mod Pathol: Off J U S Can Acad Pathol, Inc 30(6):826–833Google Scholar
  165. Wimberly H, Brown JR, Schalper K et al (2015) PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res 3(4):326–332CrossRefGoogle Scholar
  166. Workman CJ, Wang Y, El Kasmi KC et al (2009) LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol (Baltimore, Md: 1950) 182(4):1885–1891Google Scholar
  167. Wu C, Zhu Y, Jiang J, Zhao J, Zhang X-G, Xu N (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108(1):19–24CrossRefGoogle Scholar
  168. Xing X, Guo J, Wen X et al (2018) Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology 7(3):e1356144CrossRefGoogle Scholar
  169. Yang W, Song Y, Lu Y-L, Sun J-Z, Wang H-W (2013) Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia. Immunology 139(4):513–522CrossRefPubMedPubMedCentralGoogle Scholar
  170. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC (2014) Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer 50(7):1361–1369CrossRefGoogle Scholar
  171. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC (2016) Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma. Eur J Cancer 57:91–103CrossRefGoogle Scholar
  172. Yearley JH, Gibson C, Yu N et al (2017) PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Cancer Res 23(12):3158–3167CrossRefGoogle Scholar
  173. Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J (2015) Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol, Immunother: CII 64(7):853–860CrossRefGoogle Scholar
  174. Zang X, Thompson RH, Al-Ahmadie HA et al (2007) B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 104(49):19458–19463CrossRefGoogle Scholar
  175. Zeng Y, Wang CL, Xian J et al (2019) Positive correlation between programmed death ligand-1 and p53 in triple-negative breast cancer. Onco Targets Ther 12:7193–7201CrossRefPubMedPubMedCentralGoogle Scholar
  176. Zhang T, Tan XL, Xu Y, Wang ZZ, Xiao CH, Liu R (2017) Expression and prognostic value of indoleamine 2,3-dioxygenase in pancreatic cancer. Chin Med J 130(6):710–716CrossRefPubMedPubMedCentralGoogle Scholar
  177. Zhang Y, Liu YD, Luo YL et al (2018) prognostic value of lymphocyte activation gene-3 (LAG-3) expression in esophageal squamous cell carcinoma. J Cancer 9(22):4287–4293CrossRefPubMedPubMedCentralGoogle Scholar
  178. Zhao X, Kallakury B, Chahine JJ et al (2019) Surgical resection of SCLC: prognostic factors and the tumor microenvironment. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer 14(5):914–923CrossRefGoogle Scholar
  179. Zhu AX, Finn RS, Edeline J et al (2018) Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 19(7):940–952CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Wenhua Li
    • 1
    Email author
  • Jingbo Qie
    • 2
  • Yao Zhang
    • 1
  • Jinjia Chang
    • 1
  1. 1.Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Institutes of Biomedical Sciences, Fudan UniversityShanghaiChina

Personalised recommendations