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PD-L1 as a biomarker of response to immune-checkpoint inhibitors

Abstract

Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20–40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.

Key points

  • The clinical utility of PD-L1 testing varies greatly between cancer types and treatment settings.

  • The selection of specific PD-L1 assays for testing should be fit-for-purpose and determined by clinical utility; testing should be organ-specific and selected based on consultation between oncologists and pathologists.

  • While multiple commercial PD-L1 assays are available, these are not equal in terms of analytical performance and care should be taken in the interpretation of results given these differences.

  • Pre-analytical and analytical factors, scoring algorithms, and the site and timing of tissue acquisition can all influence the results of PD-L1 testing.

  • Further standardization of PD-L1 laboratory-based assay development and reporting is warranted.

  • The prospective internal review of assay performance and participation in external quality assurance programmes is recommended.

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Fig. 1: PD-L1 scoring formulas.
Fig. 2: Analytical comparison of percentage tumour cell staining, by patient, for each assay.
Fig. 3: Comparative staining features of five PD-L1 IHC assays on the same NSCLC sample.
Fig. 4: A proposed approach to assay standardization.

References

  1. 1.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Blank, C., Gajewski, T. F. & Mackensen, A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol. Immunother. 54, 307–314 (2005).

    CAS  PubMed  Google Scholar 

  4. 4.

    Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    CAS  PubMed  Google Scholar 

  5. 5.

    Gong, 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 6, 8 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Garon, E. B. et al. Five-year overall survival for patients with advanced non–small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J. Clin. Oncol. 37, 2518–2527 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Brahmer, J. R. et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J. Immunother. Cancer 6, 75 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hamid, O. et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Scheerens, H. et al. Current status of companion and complementary diagnostics: strategic considerations for development and launch. Clin. Transl Sci. 10, 84–92 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ritzhaupt, A., Hayes, I. & Ehmann, F. Implementing the EU in vitro diagnostic regulation - a European regulatory perspective on companion diagnostics. Expert Rev. Mol. Diagn. 20, 565–567 (2020).

    CAS  PubMed  Google Scholar 

  13. 13.

    US Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). FDA https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools (2020).

  14. 14.

    US Food and Drug Administration. Summary of safety and effectiveness data (SSED) for PD-L1 IHC 28-8 pharmDx. FDA http://www.accessdata.fda.gov/cdrh_docs/pdf15/p150025b.pdf (2015).

  15. 15.

    US Food and Drug Administration. Summary of safety and effectiveness data (SSED) for VENTANA PD-L1 (SP142) assay. FDA http://www.accessdata.fda.gov/cdrh_docs/pdf16/p160006b.pdf (2016).

  16. 16.

    US Food and Drug Administration. Durvalumab (Imfinzi). FDA https://www.fda.gov/drugs/resources-information-approved-drugs/durvalumab-imfinzi (2017).

  17. 17.

    Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl Med. 4, 127ra137 (2012).

    Google Scholar 

  18. 18.

    Phillips, T. et al. Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer. Appl. Immunohistochem. Mol. Morphol. 23, 541–549 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Dolled-Filhart, M. et al. Development of a prototype immunohistochemistry assay to measure programmed death ligand-1 expression in tumor tissue. Arch. Pathol. Lab. Med. 140, 1259–1266 (2016).

    CAS  PubMed  Google Scholar 

  20. 20.

    Kerr, K. M. et al. Programmed death-ligand 1 immunohistochemistry in lung cancer: in what state is this art? J. Thorac. Oncol. 10, 985–989 (2015).

    CAS  PubMed  Google Scholar 

  21. 21.

    Kerr, K. M. & Hirsch, F. R. Programmed death ligand-1 immunohistochemistry: friend or foe? Arch. Pathol. Lab. Med. 140, 326–331 (2016).

    CAS  PubMed  Google Scholar 

  22. 22.

    Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    CAS  PubMed  Google Scholar 

  23. 23.

    Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    CAS  PubMed  Google Scholar 

  24. 24.

    Vennapusa, B. et al. Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for atezolizumab. Appl. Immunohistochem. Mol. Morphol. 27, 92–100 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ott, P. A. et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J. Clin. Oncol. 35, 2535–2541 (2017).

    CAS  PubMed  Google Scholar 

  26. 26.

    Powles, T. et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 3, e172411 (2017).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kulangara, K. et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab. Med. 143, 330–337 (2019).

    CAS  PubMed  Google Scholar 

  28. 28.

    Park, Y. et al. PD-L1 testing in gastric cancer by the combined positive score of the 22C3 PharmDx and SP263 assay with clinically relevant cut-offs. Cancer Res. Treat. 52, 661–670 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tsao, M. S. et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J. Thorac. Oncol. 13, 1302–1311 (2018).

    PubMed  Google Scholar 

  30. 30.

    Liu, Y. et al. Immune cell PD-L1 colocalizes with macrophages and is associated with outcome in PD-1 pathway blockade therapy. Clin. Cancer Res. 26, 970–977 (2020).

    CAS  PubMed  Google Scholar 

  31. 31.

    Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Google Scholar 

  32. 32.

    Sul, J. et al. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist 21, 643–650 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).

    CAS  PubMed  Google Scholar 

  34. 34.

    Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    US Food and Drug Administration. Pembrolizumab (KEYTRUDA) checkpoint inhibitor. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-checkpoint-inhibitor (2016).

  36. 36.

    Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Rittmeyer, A. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389, 255–265 (2017).

    PubMed  Google Scholar 

  38. 38.

    Ratcliffe, M. J. et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer. Clin. Cancer Res. 23, 3585–3591 (2017).

    CAS  PubMed  Google Scholar 

  39. 39.

    Cooper, W. A. et al. Intra- and interobserver reproducibility assessment of PD-L1 biomarker in non-small cell lung cancer. Clin. Cancer Res. 23, 4569–4577 (2017).

    CAS  PubMed  Google Scholar 

  40. 40.

    Brunnström, H. et al. PD-L1 immunohistochemistry in clinical diagnostics of lung cancer: inter-pathologist variability is higher than assay variability. Mod. Pathol. 30, 1411–1421 (2017).

    PubMed  Google Scholar 

  41. 41.

    Robinson, M. et al. Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work. J. Pathol. Clin. Res. 5, 91–99 (2019).

    PubMed  Google Scholar 

  42. 42.

    Fitzgibbons, P. L. et al. Principles of analytic validation of immunohistochemical assays: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch. Pathol. Lab. Med. 138, 1432–1443 (2014).

    PubMed  Google Scholar 

  43. 43.

    Aeffner, F. et al. Digital microscopy, image analysis, and virtual slide repository. ILAR J. 59, 66–79 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    US Food and Drug Administration. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%). FDA https://www.fda.gov/drugs/fda-expands-pembrolizumab-indication-first-line-treatment-nsclc-tps-1 (2019).

  45. 45.

    Mok, T. S. K. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393, 1819–1830 (2019).

    CAS  PubMed  Google Scholar 

  46. 46.

    European Society for Medical Oncology. EMA does not recommend extending the use of pembrolizumab. ESMO https://www.esmo.org/oncology-news/ema-does-not-recommend-extending-the-use-of-pembrolizumab (2020).

  47. 47.

    Travis, W. D. et al. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart (IARC Press, 2015).

  48. 48.

    Aguilar, E. J. et al. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann. Oncol. 30, 1653–1659 (2019).

    CAS  PubMed  Google Scholar 

  49. 49.

    Reuss, J. E. et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J. Immunother. Cancer 8, e001282 (2020).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Hirsch, F. R. et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J. Thorac. Oncol. 12, 208–222 (2017).

    PubMed  Google Scholar 

  51. 51.

    Rimm, D. L. et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 3, 1051–1058 (2017).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Grote, H. J. et al. Programmed death-ligand 1 immunohistochemistry assay comparison studies in NSCLC: characterization of the 73-10 assay. J. Thorac. Oncol. 15, 1306–1316 (2020).

    CAS  PubMed  Google Scholar 

  53. 53.

    Torlakovic, E. et al. “Interchangeability” of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy. Mod. Pathol. 33, 4–17 (2020).

    PubMed  Google Scholar 

  54. 54.

    Torlakovic, E. et al. Canadian multicenter project on standardization of programmed death-ligand 1 immunohistochemistry 22C3 laboratory-developed tests for pembrolizumab therapy in NSCLC. J. Thorac. Oncol. 15, 1328–1337 (2020).

    CAS  PubMed  Google Scholar 

  55. 55.

    Boothman, A. M. et al. Impact of patient characteristics, prior therapy, and sample type on tumor cell programmed cell death ligand 1 expression in patients with advanced NSCLC screened for the ATLANTIC study. J. Thorac. Oncol. 14, 1390–1399 (2019).

    CAS  PubMed  Google Scholar 

  56. 56.

    Calles, A. et al. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS-mutant lung cancer. J. Thorac. Oncol. 10, 1726–1735 (2015).

    CAS  PubMed  Google Scholar 

  57. 57.

    Kim, S. et al. Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur. J. Cancer 75, 141–149 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

    Kim, H. R. et al. Concordance of programmed death-ligand 1 expression between primary and metastatic non-small cell lung cancer by immunohistochemistry and RNA in situ hybridization. Oncotarget 8, 87234–87243 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Pichler, R. et al. PD-L1 expression in bladder cancer and metastasis and its influence on oncologic outcome after cystectomy. Oncotarget 8, 66849–66864 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Uruga, H. et al. Programmed cell death ligand (PD-L1) expression in stage II and III lung adenocarcinomas and nodal metastases. J. Thorac. Oncol. 12, 458–466 (2017).

    PubMed  Google Scholar 

  61. 61.

    Téglási, V. et al. PD-L1 expression of lung cancer cells, unlike infiltrating immune cells, is stable and unaffected by therapy during brain metastasis. Clin. Lung Cancer 20, 363–369.e2 (2019).

    PubMed  Google Scholar 

  62. 62.

    Mansfield, A. S. et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann. Oncol. 27, 1953–1958 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Sheffield, B. S. et al. Investigation of PD-L1 biomarker testing methods for PD-1 axis inhibition in non-squamous non-small cell lung cancer. J. Histochem. Cytochem. 64, 587–600 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Szekely, B. et al. Immunological differences between primary and metastatic breast cancer. Ann. Oncol. 29, 2232–2239 (2018).

    CAS  PubMed  Google Scholar 

  65. 65.

    Hong, L. et al. Programmed death-ligand 1 heterogeneity and its impact on benefit from immune checkpoint inhibitors in NSCLC. J. Thorac. Oncol. 15, 1449–1459 (2020).

    CAS  PubMed  Google Scholar 

  66. 66.

    Cho, J. H. et al. Programmed death ligand 1 expression in paired non-small cell lung cancer tumor samples. Clin. Lung Cancer 18, e473–e479 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    Rojkó, L. et al. Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients. J. Cancer Res. Clin. Oncol. 144, 1219–1226 (2018).

    PubMed  Google Scholar 

  68. 68.

    Sheng, J. et al. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci. Rep. 6, 20090 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Erlmeier, F. et al. The role of PD-L1 expression and intratumoral lymphocytes in response to perioperative chemotherapy for urothelial carcinoma. Bladder Cancer 2, 425–432 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Scorer, P. et al. Consistency of tumor and immune cell programmed cell death ligand-1 expression within and between tumor blocks using the VENTANA SP263 assay. Diagn. Pathol. 13, 47 (2018).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Haragan, A. et al. Heterogeneity of PD-L1 expression in non-small cell lung cancer: implications for specimen sampling in predicting treatment response. Lung Cancer 134, 79–84 (2019).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ng Kee Kwong, F. et al. Expression of PD-L1 correlates with pleomorphic morphology and histological patterns of non-small-cell lung carcinomas. Histopathology 72, 1024–1032 (2018).

    PubMed  Google Scholar 

  73. 73.

    Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Gniadek, T. J. et al. Heterogeneous expression of PD-L1 in pulmonary squamous cell carcinoma and adenocarcinoma: implications for assessment by small biopsy. Mod. Pathol. 30, 530–538 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Munari, E. et al. PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability. Oncotarget 8, 90123–90131 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Ilie, M. et al. 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. 27, 147–153 (2016).

    CAS  PubMed  Google Scholar 

  77. 77.

    Heymann, J. J. et al. PD-L1 expression in non-small cell lung carcinoma: comparison among cytology, small biopsy, and surgical resection specimens. Cancer Cytopathol. 125, 896–907 (2017).

    CAS  PubMed  Google Scholar 

  78. 78.

    Russell-Goldman, E., Kravets, S., Dahlberg, S. E., Sholl, L. M. & Vivero, M. Cytologic-histologic correlation of programmed death-ligand 1 immunohistochemistry in lung carcinomas. Cancer Cytopathol. 126, 253–263 (2018).

    CAS  PubMed  Google Scholar 

  79. 79.

    Noll, B. et al. Programmed death ligand 1 testing in non-small cell lung carcinoma cytology cell block and aspirate smear preparations. Cancer Cytopathol. 126, 342–352 (2018).

    CAS  PubMed  Google Scholar 

  80. 80.

    Ilie, M. et al. Use of the 22C3 anti-programmed death-ligand 1 antibody to determine programmed death-ligand 1 expression in cytology samples obtained from non-small cell lung cancer patients. Cancer Cytopathol. 126, 264–274 (2018).

    CAS  PubMed  Google Scholar 

  81. 81.

    Naito, T. et al. A minimum of 100 tumor cells in a single biopsy sample is required to assess programmed cell death ligand 1 expression in predicting patient response to nivolumab treatment in nonsquamous non-small cell lung carcinoma. J. Thorac. Oncol. 14, 1818–1827 (2019).

    CAS  PubMed  Google Scholar 

  82. 82.

    Gagné, A. et al. Impact of specimen characteristics on PD-L1 testing in non-small cell lung cancer: validation of the IASLC PD-L1 testing recommendations. J. Thorac. Oncol. 14, 2062–2070 (2019).

    PubMed  Google Scholar 

  83. 83.

    Chen, Y. L. et al. Novel circulating tumor cell-based blood test for the assessment of PD-L1 protein expression in treatment-naïve, newly diagnosed patients with non-small cell lung cancer. Cancer Immunol. Immunother. 68, 1087–1094 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Tsao, M. S., Kerr, K. M., Dacic, S., Yatabe, Y. & Hirsch, F. IASLC atlas of PD-L1 immunohistochemistry testing in lung cancer. (International Association for the Study of Lung Cancer, 2017).

  85. 85.

    Strickland, A. L., Blacketer, S., Molberg, K., Markantonis, J. & Lucas, E. Effects of decalcifying agents of variable duration on PD-L1 immunohistochemistry. Am. J. Clin. Pathol. 153, 258–265 (2020).

    CAS  PubMed  Google Scholar 

  86. 86.

    Martinez-Morilla, S. et al. Quantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray. Lab. Invest. 100, 4–15 (2020).

    CAS  PubMed  Google Scholar 

  87. 87.

    Reck, M. et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J. Clin. Oncol. 37, 537–546 (2019).

    CAS  PubMed  Google Scholar 

  88. 88.

    Spigel, D. et al. IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC. Ann. Oncol. 30, v915 (2019).

    Google Scholar 

  89. 89.

    Gadgeel, S. et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 38, 1505–1517 (2020).

    CAS  PubMed  Google Scholar 

  90. 90.

    Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    CAS  PubMed  Google Scholar 

  91. 91.

    Jotte, R. et al. Atezolizumab in combination with carboplatin and Nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J. Thorac. Oncol. 15, 1351–1360 (2020).

    CAS  PubMed  Google Scholar 

  92. 92.

    Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    CAS  PubMed  Google Scholar 

  93. 93.

    Paz-Ares, L. et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N. Engl. J. Med. 379, 2040–2051 (2018).

    CAS  PubMed  Google Scholar 

  94. 94.

    Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    CAS  PubMed  Google Scholar 

  95. 95.

    US Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1 (2020).

  96. 96.

    Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).

    CAS  PubMed  Google Scholar 

  97. 97.

    Tsuruoka, K. et al. PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer 108, 115–120 (2017).

    PubMed  Google Scholar 

  98. 98.

    Yasuda, Y., Ozasa, H. & Kim, Y. H. PD-L1 expression in small cell lung cancer. J. Thorac. Oncol. 13, e40–e41 (2018).

    PubMed  Google Scholar 

  99. 99.

    Doyle, A. et al. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J. Exp. Med. 161, 1135–1151 (1985).

    CAS  PubMed  Google Scholar 

  100. 100.

    Antonia, S. et al. 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, 883–895 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    US Food and Drug Administration. FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-nivolumab-accelerated-approval-third-line-treatment-metastatic-small-cell-lung-cancer (2018).

  102. 102.

    Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Chung, H. C. et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. J. Thorac. Oncol. 15, 618–627 (2020).

    CAS  PubMed  Google Scholar 

  104. 104.

    Paz-Ares, L. et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394, 1929–1939 (2019).

    CAS  PubMed  Google Scholar 

  105. 105.

    Kaunitz, G. J. et al. Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab. Invest. 97, 1063–1071 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Kraft, S., Fernandez-Figueras, M. T., Richarz, N. A., Flaherty, K. T. & Hoang, M. P. PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression. J. Am. Acad. Dermatol. 77, 534–542 (2017).

    CAS  PubMed  Google Scholar 

  107. 107.

    Madore, J. et al. PD-L1 negative status is associated with lower mutation burden, differential expression of immune-related genes, and worse survival in stage III melanoma. Clin. Cancer Res. 22, 3915–3923 (2016).

    CAS  PubMed  Google Scholar 

  108. 108.

    Kakavand, H. et al. PD-L1 expression and immune escape in melanoma resistance to MAPK inhibitors. Clin. Cancer Res. 23, 6054–6061 (2017).

    CAS  PubMed  Google Scholar 

  109. 109.

    Obeid, J. M. et al. PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 5, e1235107 (2016).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Gandini, S., Massi, D. & Mandalà, M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 100, 88–98 (2016).

    PubMed  Google Scholar 

  111. 111.

    Phillips, T. et al. Development of a diagnostic programmed cell death 1-ligand 1 immunohistochemistry assay for nivolumab therapy in melanoma. Appl. Immunohistochem. Mol. Morphol. 26, 6–12 (2018).

    CAS  PubMed  Google Scholar 

  112. 112.

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  Google Scholar 

  113. 113.

    Schachter, J. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390, 1853–1862 (2017).

    CAS  PubMed  Google Scholar 

  114. 114.

    Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Hodi, F. S. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 19, 1480–1492 (2018).

    CAS  PubMed  Google Scholar 

  116. 116.

    US Food and Drug Administration. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma (2020).

  117. 117.

    Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable Hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    CAS  PubMed  Google Scholar 

  118. 118.

    Lee, M. S. et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 21, 808–820 (2020).

    CAS  PubMed  Google Scholar 

  119. 119.

    Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).

    PubMed  Google Scholar 

  120. 120.

    Yau, T. et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 30, v874–v875 (2019).

    Google Scholar 

  121. 121.

    US Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative (2020).

  122. 122.

    Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

    CAS  Google Scholar 

  123. 123.

    Reisenbichler, E. S. et al. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer. Mod. Pathol. 33, 1746–1752 (2020).

    CAS  PubMed  Google Scholar 

  124. 124.

    Bera, K., Schalper, K. A., Rimm, D. L., Velcheti, V. & Madabhushi, A. Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology. Nat. Rev. Clin. Oncol. 16, 703–715 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Cortes, J. et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J. Clin. Oncol. 38 (Suppl. 15), 1000 (2020).

    Google Scholar 

  126. 126.

    US Food and Drug Administration. PD-L1 IHC 22C3 pharmDx. FDA https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150013S014C.pdf (2019).

  127. 127.

    Larkins, E. et al. FDA approval summary: pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy. Oncologist 22, 873–878 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Cohen, E. E. W. et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393, 156–167 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Ferris, R. L. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856–1867 (2016).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Burtness, B. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394, 1915–1928 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    US Food and Drug Administration. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-first-line-treatment-head-and-neck-squamous-cell-carcinoma (2019).

  132. 132.

    Cohen, E. E. W. et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J. Immunother. Cancer 7, 184 (2019).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Ma, J. et al. PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). Diagn. Pathol. 13, 91 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Angell, H. K. et al. PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology 8, e1544442 (2019).

    CAS  PubMed  Google Scholar 

  135. 135.

    Sun, Y. et al. Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer. Cancer Manag. Res. 11, 6397–6410 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Kawazoe, A. et al. Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer. Gastric Cancer 22, 69–76 (2019).

    CAS  PubMed  Google Scholar 

  137. 137.

    Liu, X. et al. High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features. Pathol. Res. Pract. 216, 152881 (2020).

    CAS  PubMed  Google Scholar 

  138. 138.

    Wang, L. et al. Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status. Cancer Med. 7, 2612–2620 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Fang, W. et al. Association between PD-L1 expression on tumour-infiltrating lymphocytes and overall survival in patients with gastric cancer. J. Cancer 8, 1579–1585 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Seo, A. N. et al. Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer. Br. J. Cancer 117, 1753–1760 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Wang, W. et al. Immunoclassification characterized by CD8 and PD-L1 expression is associated with the clinical outcome of gastric cancer patients. Oncotarget 9, 12164–12173 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Wu, Y. et al. PD-1 and PD-L1 co-expression predicts favorable prognosis in gastric cancer. Oncotarget 8, 64066–64082 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Zayac, A. & Almhanna, K. Esophageal, gastric cancer and immunotherapy: small steps in the right direction? Transl Gastroenterol. Hepatol. 5, 9 (2020).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Fuchs, C. S. et al. 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, e180013 (2018).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Fashoyin-Aje, L. et al. FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1. Oncologist 24, 103–109 (2019).

    CAS  PubMed  Google Scholar 

  146. 146.

    Shitara, K. et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392, 123–133 (2018).

    CAS  PubMed  Google Scholar 

  147. 147.

    Tabernero, J. et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study. J. Clin. Oncol. 37, LBA4007 (2019).

    Google Scholar 

  148. 148.

    Jiang, Y. et al. Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma. Oncotarget 8, 30175–30189 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Duan, J. et al. A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy. J. Immunother. Cancer 6, 100 (2018).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Yu, W. & Guo, Y. Prognostic significance of programmed death ligand-1 immunohistochemical expression in esophageal cancer: a meta-analysis of the literature. Medicine 97, e11614 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Jiang, D. et al. Independent prognostic role of PD-L1expression in patients with esophageal squamous cell carcinoma. Oncotarget 8, 8315–8329 (2017).

    PubMed  Google Scholar 

  152. 152.

    Shah, M. A. et al. 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 Oncol. 5, 546–550 (2019).

    PubMed  Google Scholar 

  153. 153.

    Shah, M. A. et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase 3 KEYNOTE-181 study. J. Clin. Oncol. 37, 4010–4010 (2019).

    Google Scholar 

  154. 154.

    US Food and Drug Administration. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-esophageal-squamous-cell-cancer#:~:text=On%20July%2030%2C%202019%2C%20the,FDA%2Dapproved%20test%2C%20with%20disease (2019).

  155. 155.

    Sharma, P. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 18, 312–322 (2017).

    CAS  PubMed  Google Scholar 

  156. 156.

    Rosenberg, J. E. et al. 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 387, 1909–1920 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).

    CAS  PubMed  Google Scholar 

  159. 159.

    Balar, A. V. et al. 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, 1483–1492 (2017).

    CAS  PubMed  Google Scholar 

  160. 160.

    Vuky, J. et al. Long-term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J. Clin. Oncol. 38, 2658–2666 (2020).

    CAS  PubMed  Google Scholar 

  161. 161.

    Ning, Y. M. et al. FDA approval summary: atezolizumab for the treatment of patients with progressive advanced urothelial carcinoma after platinum-containing chemotherapy. Oncologist 22, 743–749 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Suzman, D. L. et al. FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy. Oncologist 24, 563–569 (2019).

    CAS  PubMed  Google Scholar 

  163. 163.

    US Food and Drug Administration. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients (2018).

  164. 164.

    US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment (2020).

  165. 165.

    Powles, T. et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN bladder 100 phase III interim analysis. J. Clin. Oncol. 38, LBA1-LBA1 (2020).

    Google Scholar 

  166. 166.

    Tabayoyong, W. & Gao, J. The emerging role of immunotherapy in advanced urothelial cancers. Curr. Opin. Oncol. 30, 172–180 (2018).

    CAS  PubMed  Google Scholar 

  167. 167.

    Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Rini, B. I. et al. Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    CAS  Google Scholar 

  169. 169.

    Motzer, R. J. et al. Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Davis, A. A. & Patel, V. G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US food and drug administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7, 278 (2019).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Gjoerup, O. et al. Identification and utilization of biomarkers to predict response to immune checkpoint inhibitors. AAPS J. 22, 132 (2020).

    PubMed  Google Scholar 

  172. 172.

    Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    CAS  PubMed  Google Scholar 

  173. 173.

    Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors (2020).

  174. 174.

    Gandara, D. R. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat. Med. 24, 1441–1448 (2018).

    CAS  PubMed  Google Scholar 

  175. 175.

    Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Ramalingam, S. S. et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 part 1. J. Clin. Oncol. 38, 9500–9500 (2020).

    Google Scholar 

  177. 177.

    Maibach, F., Sadozai, H., Seyed Jafari, S. M., Hunger, R. E. & Schenk, M. Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Front. Immunol. 11, 2105 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    van Wilpe, S. et al. Prognostic and predictive value of tumor-infiltrating immune cells in urothelial cancer of the bladder. Cancers 12, 2692 (2020).

    PubMed Central  Google Scholar 

  179. 179.

    Gettinger, S. N. et al. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat. Commun. 9, 3196 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Teng, M. W., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Ben Dori, S., Aizic, A., Sabo, E. & Hershkovitz, D. Spatial heterogeneity of PD-L1 expression and the risk for misclassification of PD-L1 immunohistochemistry in non-small cell lung cancer. Lung Cancer 147, 91–98 (2020).

    PubMed  Google Scholar 

  183. 183.

    Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Chen, S. et al. Mechanisms regulating PD-L1 expression on tumor and immune cells. J. Immunother. Cancer 7, 305 (2019).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Akbay, E. A. et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3, 1355–1363 (2013).

    CAS  PubMed  Google Scholar 

  186. 186.

    Leduc, C. et al. TPF induction chemotherapy increases PD-L1 expression in tumour cells and immune cells in head and neck squamous cell carcinoma. ESMO Open 3, e000257 (2018).

    PubMed  PubMed Central  Google Scholar 

  187. 187.

    Lim, Y. J. et al. Chemoradiation-induced alteration of programmed death-ligand 1 and CD8+ tumor-infiltrating lymphocytes identified patients with poor prognosis in rectal cancer: a matched comparison analysis. Int. J. Radiat. Oncol. Biol. Phys. 99, 1216–1224 (2017).

    PubMed  Google Scholar 

  188. 188.

    Parra, E. R. et al. Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches. J. Immunother. Cancer 6, 48 (2018).

    PubMed  PubMed Central  Google Scholar 

  189. 189.

    Guibert, N. et al. PD-L1 expression in circulating tumor cells of advanced non-small cell lung cancer patients treated with nivolumab. Lung Cancer 120, 108–112 (2018).

    PubMed  Google Scholar 

  190. 190.

    Ilié, M. et al. Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer. Ann. Oncol. 29, 193–199 (2018).

    PubMed  Google Scholar 

  191. 191.

    Janning, M. et al. Determination of PD-L1 expression in circulating tumor cells of NSCLC patients and correlation with response to PD-1/PD-L1 inhibitors. Cancers 11, 835 (2019).

    CAS  PubMed Central  Google Scholar 

  192. 192.

    Del Re, M. et al. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br. J. Cancer 118, 820–824 (2018).

    PubMed  PubMed Central  Google Scholar 

  193. 193.

    Gong, B. et al. Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer. J. Exp. Med. 216, 982–1000 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Ahmed, F. S. et al. PD-L1 protein expression on both tumor cells and macrophages are associated with response to neoadjuvant durvalumab with chemotherapy in triple-negative breast cancer. Clin. Cancer Res. 26, 5456–5461 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Lantuejoul, S. et al. PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee. J. Thorac. Oncol. 15, 499–519 (2020).

    CAS  PubMed  Google Scholar 

  196. 196.

    Walk, E. E. et al. The cancer immunotherapy biomarker testing landscape. Arch. Pathol. Lab. Med. 144, 706–724 (2020).

    CAS  PubMed  Google Scholar 

  197. 197.

    Rimm, D. L. et al. Reanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer. Breast Cancer Res. 21, 72 (2019).

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Munari, E. et al. PD-L1 assays 22C3 and SP263 are not interchangeable in non-small cell lung cancer when considering clinically relevant cutoffs: an interclone evaluation by differently trained pathologists. Am. J. Surg. Pathol. 42, 1384–1389 (2018).

    PubMed  Google Scholar 

  199. 199.

    Chung, H. C. et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 37, 1470–1478 (2019).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Adrian Sacher, Princess Margaret Cancer Center, Toronto, ON, Canada, for input to the manuscript.

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D.B.D. has acted as a consultant of Boehringer Ingelheim. L.M.S. has acted as a consultant of AstraZeneca, EMD Serono, and Genentech and has received research funding (through Harvard Medical School) from Genentech. K.M.K. has acted as a consultant of AbbVie, Amgen, AstraZeneca, Archer Diagnostics, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Roche Diagnostics/Ventana and has received speaker’s fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Roche Diagnostics/Ventana, Medscape, Prime Oncology, and PeerVoice. S.G. has acted as a consultant and/or advisor of Merck and OncoMed and has received research funding from Agenus, Bristol-Myers Squibb, Genentech, Immune Design, Janssen R&D, Pfizer, Regeneron, and Takeda as well as being a named co-inventor on a patent relating to the use of multiplex immunohistochemistry to characterize tumours and treatment responses. This patent is filed through Icahn School of Medicine at Mount Sinai (ISMMS) and non-exclusively licensed to Caprion. ISMMS has received payments associated with the licensing of this technology and both ISMMS and S.G. are entitled to future payments. M.S.T. has acted as a consultant of AstraZeneca, Bristol-Myers Squibb, and Merck and has received a research grant (through the University Health Network) from Merck. F.R.H. has acted as an advisor of Amgen, AstraZeneca/Daiichi, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, OncoCyte, Regeneron/Sanofi, and Ventana and has received research grants (through University of Colorado) from Abbvie, Amgen, Bayer, Biodesix, Cetya Pharmaceuticals, Dako, Leica, Merck, Rain Therapeutics and Ventana. The other authors declare no competing interests.

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Doroshow, D.B., Bhalla, S., Beasley, M.B. et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 18, 345–362 (2021). https://doi.org/10.1038/s41571-021-00473-5

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