Skip to main content

Advertisement

SpringerLink
Log in

Predictive biomarkers for response to immune checkpoint inhibitors in lung cancer: PD-L1 and beyond

  • Review and Perspectives
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Immune checkpoint inhibitor (ICI) therapies, including the programmed cell death protein 1 (PD-1) axis blockade, are considered a major oncological breakthrough of the early twenty-first century and have led to remarkable response rates and survival in a subset of patients with non–small cell lung cancer (NSCLC). However, the available therapies work only for one in five unselected, advanced NSCLC patients; thus, patient selection needs to be performed with the use of efficient biomarkers. Although imperfect, programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) on tumor cells and/or immune cells has been established as a predictive biomarker for response to the PD-1 axis blockade. There remain several pre-analytical, analytical, and post-analytical issues, however, before implementing a PD-L1 IHC assay(s) in the pathology laboratory. In addition, given the lack of robust sensitivity and specificity of PD-L1 IHC for predicting response to ICIs, other biomarkers including tumor mutation burden (TMB) are under investigation. In this review, issues associated with PD-L1 IHC and TMB estimations will be discussed, and other promising biomarkers for predicting response to ICIs will be briefly introduced.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Finn OJ (2008) Cancer immunology. N Engl J Med 358:2704–2715. https://doi.org/10.1056/NEJMra072739

    Article  CAS  PubMed  Google Scholar 

  2. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012

    Article  CAS  PubMed  Google Scholar 

  3. Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467–477. https://doi.org/10.1038/nri2326

    Article  CAS  PubMed  Google Scholar 

  4. Flies DB, Chen L (2007) The new B7s: playing a pivotal role in tumor immunity. J Immunother 30:251–260. https://doi.org/10.1097/CJI.0b013e31802e085a

    Article  CAS  PubMed  Google Scholar 

  5. Huynh TG, Morales-Oyarvide V, Campo MJ, Gainor JF, Bozkurtlar E, Uruga H, Zhao L, Gomez-Caraballo M, Hata AN, Mark EJ, Lanuti M, Engelman JA, Mino-Kenudson M (2016) Programmed cell death ligand 1 expression in resected lung adenocarcinomas: association with immune microenvironment. J Thorac Oncol 11:1869–1878. https://doi.org/10.1016/j.jtho.2016.08.134

    Article  PubMed  Google Scholar 

  6. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A (2016) 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. https://doi.org/10.1016/s0140-6736(16)00587-0

    Article  CAS  PubMed  Google Scholar 

  9. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR (2017) 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. https://doi.org/10.1016/s0140-6736(16)32517-x

    Article  PubMed  Google Scholar 

  10. Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Felip E, Goldman JW, Scalzo C, Jensen E, Kush DA, Hui R (2019) 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. https://doi.org/10.1200/jco.19.00934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  12. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR (2019) 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. https://doi.org/10.1200/jco.18.00149

    Article  CAS  PubMed  Google Scholar 

  13. Cappuzzo F, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter H, Kopp H, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Archer V, Ochi Lohmann T, Wang L, Kowanetz M, Lin W, Sandler A, West H (2018) A phase III multicenter, randomized, open-label study evaluating the efficacy and safety of atezolizumab (MPDL3280A, anti-PD-L1 antibody) in combination with carboplatin+nab-paclitaxel for chemotherapy-naive patients with stage IV non-squamous non-small cell lung cancer. ESMO 2018 Congress:Abstract LBA53

  14. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005

    Article  CAS  PubMed  Google Scholar 

  15. Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, Novello S, Orlandi F, Ball S, Goldschmidt J Jr, Sanborn R, Hoang T, Mendus D, Deng Y, Kowanetz M, Wen X, Lin W, Sandler A, Nishio M (2018) IMpower132: PFS and safety results with 1 L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol 13:S332–S333

    Article  Google Scholar 

  16. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040–2051. https://doi.org/10.1056/NEJMoa1810865

    Article  CAS  PubMed  Google Scholar 

  17. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288–2301. https://doi.org/10.1056/NEJMoa1716948

    Article  CAS  PubMed  Google Scholar 

  18. West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:924–937. https://doi.org/10.1016/s1470-2045(19)30167-6

    Article  CAS  PubMed  Google Scholar 

  19. Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora JE, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS (2019) Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 381:2020–2031. https://doi.org/10.1056/NEJMoa1910231

    Article  CAS  PubMed  Google Scholar 

  20. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro CJ, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M (2018) Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342–2350. https://doi.org/10.1056/NEJMoa1809697

    Article  CAS  PubMed  Google Scholar 

  21. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379:2220–2229. https://doi.org/10.1056/NEJMoa1809064

    Article  CAS  PubMed  Google Scholar 

  22. Network NCC (2020) NCCN clinical practice guidelines oncology in non-small cell lung cancer. The National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 23 Jan 2021

  23. Network NCC (2020) NCCN clinical practice guidelines oncology in small cell lung cancer. The National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed 23 Jan 2021

  24. Uprety D, Mandrekar SJ, Wigle D, Roden AC, Adjei AA (2020) Neoadjuvant immunotherapy for NSCLC: current concepts and future approaches. J Thorac Oncol 15:1281–1297. https://doi.org/10.1016/j.jtho.2020.05.020

    Article  CAS  PubMed  Google Scholar 

  25. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Paz-Ares L, Spira A, Raben D, Planchard D, Cho BC, Özgüroğlu M, Daniel D, Villegas A, Vicente D, Hui R, Murakami S, Spigel D, Senan S, Langer CJ, Perez BA, Boothman AM, Broadhurst H, Wadsworth C, Dennis PA, Antonia SJ, Faivre-Finn C (2020) Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol 31:798–806. https://doi.org/10.1016/j.annonc.2020.03.287

    Article  CAS  PubMed  Google Scholar 

  27. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. Administration USFaD (2020) https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc. Accessed 23 Jan 2021

  28. Lantuejoul S, Sound-Tsao M, Cooper WA, Girard N, Hirsch FR, Roden AC, Lopez-Rios F, Jain D, Chou TY, Motoi N, Kerr KM, Yatabe Y, Brambilla E, Longshore J, Papotti M, Sholl LM, Thunnissen E, Rekhtman N, Borczuk A, Bubendorf L, Minami Y, Beasley MB, Botling J, Chen G, Chung JH, Dacic S, Hwang D, Lin D, Moreira A, Nicholson AG, Noguchi M, Pelosi G, Poleri C, Travis W, Yoshida A, Daigneault JB, Wistuba II, Mino-Kenudson M (2020) PD-L1 testing for lung cancer in 2019: perspective from the IASLC Pathology Committee. J Thorac Oncol 15:499–519. https://doi.org/10.1016/j.jtho.2019.12.107

    Article  CAS  PubMed  Google Scholar 

  29. Mino-Kenudson M (2016) Programmed cell death ligand-1 (PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer? Cancer Biol Med 13:157–170. https://doi.org/10.20892/j.issn.2095-3941.2016.0009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tsao M, Kerr K, Dacic S, Yatabe Y, Hirsch F, IASLC (2017) IASLC atlas of PD-L1 immunohistochemistry testing in lung cancer. Editorial Rx Press, Aurora

    Google Scholar 

  31. Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, Richardson W, Towne P, Hanks D, Vennapusa B, Mistry A, Kalamegham R, Averbuch S, Novotny J, Rubin E, Emancipator K, McCaffery I, Williams JA, Walker J, Longshore J, Tsao MS, Kerr KM (2017) 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. https://doi.org/10.1016/j.jtho.2016.11.2228

    Article  PubMed  Google Scholar 

  32. Tsao MS, Kerr KM, Kockx M, Beasley MB, Borczuk AC, Botling J, Bubendorf L, Chirieac L, Chen G, Chou TY, Chung JH, Dacic S, Lantuejoul S, Mino-Kenudson M, Moreira AL, Nicholson AG, Noguchi M, Pelosi G, Poleri C, Russell PA, Sauter J, Thunnissen E, Wistuba I, Yu H, Wynes MW, Pintilie M, Yatabe Y, Hirsch FR (2018) PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol 13:1302–1311. https://doi.org/10.1016/j.jtho.2018.05.013

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mino-Kenudson M, Redman M, Hedger J, Daigneault J, Botling J, Brambilla E, Chen G, Chou T, Cooper W, Hirsch FR, Jain D, Kerr K, Longshore J, Lopez-Rios F, Motoi N, Pelosi G, Tsao M, Yatabe Y, Beasley MB, Borczuk A, Bubendorf L, Chung J, Dacic S, Hwang D, Minami Y, Moreira A, Nicholson A, Papotti M, Poleri C, Rekhtman N, Roden AC, Russell P, Sholl L, Thunnissen E, Travis W, Yoshida A, Wynes M, Wistuba I, Lantuejoul S (2019) IASLC global survey for pathologists on PD-L1 testing for non-small cell lung cancer. J Thorac Oncol 14:S778–S779

    Article  Google Scholar 

  34. Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, Dietel M, Longshore JW, López-Ríos F, Penault-Llorca F, Viale G, Wotherspoon AC, Kerr KM, Tsao MS (2017) Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol 35:3867–3876. https://doi.org/10.1200/jco.2017.74.7642

    Article  CAS  PubMed  Google Scholar 

  35. Sterlacci W, Fiegl M, Droeser RA, Tzankov A (2016) Expression of PD-L1 identifies a subgroup of more aggressive non-small cell carcinomas of the lung. Pathobiology 83:267–275. https://doi.org/10.1159/000444804

    Article  CAS  PubMed  Google Scholar 

  36. Torlakovic E, Albadine R, Bigras G, Boag A, Bojarski A, Cabanero M, Camilleri-Broet S, Cheung C, Couture C, Craddock KJ, Cutz JC, Dhamanaskar P, Fiset PO, Hossain M, Hwang DM, Ionescu D, Itani D, Kelly MM, Kwan K, Lim HJ, Nielsen Ht S, Qing G, Sekhon H, Spatz A, Waghray R, Wang H, Xu Z, Tsao MS (2020) Canadian multicentre project on standardization of PD-L1 22C3 immunohistochemistry laboratory developed tests for pembrolizumab therapy in non-small cell lung cancer. J Thorac Oncol 15:1328–1337. https://doi.org/10.1016/j.jtho.2020.03.029

    Article  CAS  PubMed  Google Scholar 

  37. Calles A, Liao X, Sholl LM, Rodig SJ, Freeman GJ, Butaney M, Lydon C, Dahlberg SE, Hodi FS, Oxnard GR, Jackman DM, Jänne PA (2015) 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. https://doi.org/10.1097/jto.0000000000000687

    Article  CAS  PubMed  Google Scholar 

  38. Gagné A, Wang E, Bastien N, Orain M, Desmeules P, Pagé S, Trahan S, Couture C, Joubert D, Joubert P (2019) 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. https://doi.org/10.1016/j.jtho.2019.08.2503

    Article  CAS  PubMed  Google Scholar 

  39. Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, Fazzalari L, Zahaf K, Lalvée S, Washetine K, Mouroux J, Vénissac N, Poudenx M, Otto J, Sabourin JC, Marquette CH, Hofman V, Hofman P (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 27:147–153. https://doi.org/10.1093/annonc/mdv489

    Article  CAS  PubMed  Google Scholar 

  40. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, Velcheti V, Herbst R, LoRusso P, Rimm DL (2016) Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol 2:46–54. https://doi.org/10.1001/jamaoncol.2015.3638

    Article  PubMed  PubMed Central  Google Scholar 

  41. Munari E, Zamboni G, Lunardi G, Marchionni L, Marconi M, Sommaggio M, Brunelli M, Martignoni G, Netto GJ, Hoque MO, Moretta F, Mingari MC, Pegoraro MC, Inno A, Paiano S, Terzi A, Cavazza A, Rossi G, Mariotti FR, Vacca P, Moretta L, Bogina G (2018) PD-L1 expression heterogeneity in non-small cell lung cancer: defining criteria for harmonization between biopsy specimens and whole sections. J Thorac Oncol 13:1113–1120. https://doi.org/10.1016/j.jtho.2018.04.017

    Article  CAS  PubMed  Google Scholar 

  42. Zito Marino F, Rossi G, Montella M, Botti G, De Cecio R, Morabito A, La Manna C, Ronchi A, Micheli M, Salatiello G, Micheli P, Rocco D, Accardo M, Franco R (2020) Heterogeneity of PD-L1 expression in lung mixed adenocarcinomas and adenosquamous carcinomas. Am J Surg Pathol 44:378–386. https://doi.org/10.1097/pas.0000000000001400

    Article  PubMed  Google Scholar 

  43. Thunnissen E, Kerr KM, Dafni U, Bubendorf L, Finn SP, Soltermann A, Biernat W, Cheney R, Verbeken E, Warth A, Marchetti A, Speel EM, Pokharel S, Quinn AM, Monkhorst K, Navarro A, Madsen LB, Tsourti Z, Geiger T, Kammler R, Peters S, Stahel RA (2020) Programmed death-ligand 1 expression influenced by tissue sample size. Scoring based on tissue microarrays' and cross-validation with resections, in patients with, stage I-III, non-small cell lung carcinoma of the European Thoracic Oncology Platform Lungscape cohort. Mod Pathol 33:792–801. https://doi.org/10.1038/s41379-019-0383-9

    Article  CAS  PubMed  Google Scholar 

  44. Uruga H, Bozkurtlar E, Huynh TG, Muzikansky A, Goto Y, Gomez-Caraballo M, Hata AN, Gainor JF, Mark EJ, Engelman JA, Lanuti MD, Mino-Kenudson M (2017) Programmed Cell Death Ligand (PD-L1) expression in stage II and III lung adenocarcinomas and nodal metastases. J Thorac Oncol 12:458–466. https://doi.org/10.1016/j.jtho.2016.10.015

    Article  PubMed  Google Scholar 

  45. Hong L, Negrao MV, Dibaj SS, Chen R, Reuben A, Bohac JM, Liu X, Skoulidis F, Gay CM, Cascone T, Mitchell KG, Tran HT, Le X, Byers LA, Sepesi B, Altan M, Elamin YY, Fossella FV, Kurie JM, Lu C, Mott FE, Tsao AS, Rinsurongkawong W, Lewis J, Gibbons DL, Glisson BS, Blumenschein GR Jr, Roarty EB, Futreal PA, Wistuba II, Roth JA, Swisher SG, Papadimitrakopoulou VA, Heymach JV, Lee JJ, Simon GR, Zhang J (2020) Programmed Death Ligand 1 heterogeneity and its impact on benefit from immune checkpoint inhibitors in non-small-cell lung cancer. J Thorac Oncol 15:1449–1459. https://doi.org/10.1016/j.jtho.2020.04.026

    Article  CAS  PubMed  Google Scholar 

  46. Herbst RS, Baas P, Perez-Gracia JL, Felip E, Kim DW, Han JY, Molina JR, Kim JH, Dubos Arvis C, Ahn MJ, Majem M, Fidler MJ, Surmont V, de Castro G Jr, Garrido M, Shentu Y, Emancipator K, Samkari A, Jensen EH, Lubiniecki GM, Garon EB (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 30:281–289. https://doi.org/10.1093/annonc/mdy545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boothman AM, Scott M, Ratcliffe M, Whiteley J, Dennis PA, Wadsworth C, Sharpe A, Rizvi NA, Garassino MC, Walker J (2019) 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. https://doi.org/10.1016/j.jtho.2019.04.025

    Article  CAS  PubMed  Google Scholar 

  48. Skov BG, Skov T (2017) Paired comparison of PD-L1 expression on cytologic and histologic specimens from malignancies in the lung assessed with PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx. Appl Immunohistochem Mol Morphol 25:453–459. https://doi.org/10.1097/pai.0000000000000540

    Article  CAS  PubMed  Google Scholar 

  49. Noll B, Wang WL, Gong Y, Zhao J, Kalhor N, Prieto V, Staerkel G, Roy-Chowdhuri S (2018) Programmed death ligand 1 testing in non-small cell lung carcinoma cytology cell block and aspirate smear preparations. Cancer Cytopathol 126:342–352. https://doi.org/10.1002/cncy.21987

    Article  CAS  PubMed  Google Scholar 

  50. Kerr K, Tsao M, Yatabe Y, Thunnissen E, Nicholson A, Moreira A, Chou T, Borczuk A, Bubendorf L, Mino-Kenudson M, Botling J, Beasley MB, Chirieac L, Dacic S, Lantuejoul S, Pelosi G, Chung J, Chen G, Russell P, Poleri C, Sauter J, Yu H, Noguchi M, Wistuba I, Pintilie M, Wynes M, Hirsch F (2018) Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study. J Thorac Oncol 13:S325

    Article  Google Scholar 

  51. Lloyd IE, Zhou W, Witt BL, Chadwick BE (2019) Characterization of PD-L1 immunohistochemical expression in cell blocks with different specimen fixation and processing methods. Appl Immunohistochem Mol Morphol 27:107–113. https://doi.org/10.1097/pai.0000000000000572

    Article  CAS  PubMed  Google Scholar 

  52. Vigliar E, Iaccarino A, Campione S, Campanino MR, Clery E, Pisapia P, De Luca C, Bellevicine C, Malapelle U, De Dominicis G, Troncone G (2020) PD-L1 expression in cell-blocks of non-small cell lung cancer: the impact of prolonged fixation. Diagn Cytopathol 48:595–603. https://doi.org/10.1002/dc.24439

    Article  PubMed  Google Scholar 

  53. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028. https://doi.org/10.1056/NEJMoa1501824

    Article  PubMed  Google Scholar 

  54. TECENTRIQ® (atezolizumab) injection, for intravenous use. Administration USFaD (2019) https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s018lbl.pdf. Accessed 23 Jan 2021

  55. Sholl LM, Hirsch FR, Hwang D, Botling J, Lopez-Rios F, Bubendorf L, Mino-Kenudson M, Roden AC, Beasley MB, Borczuk A, Brambilla E, Chen G, Chou TY, Chung JH, Cooper WA, Dacic S, Lantuejoul S, Jain D, Lin D, Minami Y, Moreira A, Nicholson AG, Noguchi M, Papotti M, Pelosi G, Poleri C, Rekhtman N, Sound-Tsao M, Thunnissen E, Travis W, Yatabe Y, Yoshida A, Daigneault JB, Zehir A, Peters S, Wistuba II, Kerr KM, Longshore JW (2020) Tumor mutation burden: promises and challenges a perspective from the IASLC Pathology Committee. J Thorac Oncol 15:1409–1424. https://doi.org/10.1016/j.jtho.2020.05.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van’t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chae YK, Davis AA, Raparia K, Agte S, Pan A, Mohindra N, Villaflor V, Giles F (2019) Association of tumor mutational burden with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small-cell lung cancer. Clin Lung Cancer 20:88–96.e86. https://doi.org/10.1016/j.cllc.2018.09.008

    Article  CAS  PubMed  Google Scholar 

  58. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415–2426. https://doi.org/10.1056/NEJMoa1613493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jerusalem G, Chen F, Spigel D, Iannotti N, Mcclay E, Redfern C, Bennouna J, Taylor M, Kaufman H, Kelly K, Chand V, Heydebreck A, Verschraegen C (2017) JAVELIN solid tumor: safety and clinical activity of avelumab (anti-PD-L1) as first-line treatment in patients with advanced NSCLC. J Thorac Oncol 12:S252

    Article  Google Scholar 

  61. Chang H, Sasson A, Srinivasan S, Golhar R, Greenawalt DM, Geese WJ, Green G, Zerba K, Kirov S, Szustakowski J (2019) Bioinformatic methods and bridging of assay results for reliable tumor mutational burden assessment in non-small-cell lung cancer. Mol Diagn Ther 23:507–520. https://doi.org/10.1007/s40291-019-00408-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, Koyama T, Kakishima H, Kitami M, Matsushita H, Furukawa E, Narushima D, Nagai M, Taniguchi H, Motoi N, Sekine S, Maeshima A, Mori T, Watanabe R, Yoshida M, Yoshida A, Yoshida H, Satomi K, Sukeda A, Hashimoto T, Shimizu T, Iwasa S, Yonemori K, Kato K, Morizane C, Ogawa C, Tanabe N, Sugano K, Hiraoka N, Tamura K, Yoshida T, Fujiwara Y, Ochiai A, Yamamoto N, Kohno T (2019) Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: a hospital-based study. Cancer Sci 110:1480–1490. https://doi.org/10.1111/cas.13969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Alborelli I, Leonards K, Rothschild SI, Leuenberger LP, Savic Prince S, Mertz KD, Poechtrager S, Buess M, Zippelius A, Läubli H, Haegele J, Tolnay M, Bubendorf L, Quagliata L, Jermann P (2020) Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer. J Pathol 250:19–29. https://doi.org/10.1002/path.5344

    Article  CAS  PubMed  Google Scholar 

  64. Stenzinger A, Endris V, Budczies J, Merkelbach-Bruse S, Kazdal D, Dietmaier W, Pfarr N, Siebolts U, Hummel M, Herold S, Andreas J, Zoche M, Tögel L, Rempel E, Maas J, Merino D, Stewart M, Zaoui K, Schlesner M, Glimm H, Fröhling S, Allen J, Horst D, Baretton G, Wickenhauser C, Tiemann M, Evert M, Moch H, Kirchner T, Büttner R, Schirmacher P, Jung A, Haller F, Weichert W, Dietel M (2020) Harmonization and standardization of panel-based tumor mutational burden measurement: real-world results and recommendations of the quality in pathology study. J Thorac Oncol 15:1177–1189. https://doi.org/10.1016/j.jtho.2020.01.023

    Article  CAS  PubMed  Google Scholar 

  65. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104. https://doi.org/10.1056/NEJMoa1801946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Domblides C, Leroy K, Monnet I, Mazières J, Barlesi F, Gounant V, Baldacci S, Mennecier B, Toffart AC, Audigier-Valette C, Doucet L, Giroux-Leprieur E, Guisier F, Ricordel C, Molinier O, Perol M, Pichon E, Robinet G, Templement-Grangerat D, Ruppert AM, Rabbe N, Antoine M, Wislez M (2020) Efficacy of immune checkpoint inhibitors in lung sarcomatoid carcinoma. J Thorac Oncol 15:860–866. https://doi.org/10.1016/j.jtho.2020.01.014

    Article  CAS  PubMed  Google Scholar 

  67. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A, Kaley TJ, Kendall SM, Motzer RJ, Hakimi AA, Voss MH, Russo P, Rosenberg J, Iyer G, Bochner BH, Bajorin DF, Al-Ahmadie HA, Chaft JE, Rudin CM, Riely GJ, Baxi S, Ho AL, Wong RJ, Pfister DG, Wolchok JD, Barker CA, Gutin PH, Brennan CW, Tabar V, Mellinghoff IK, DeAngelis LM, Ariyan CE, Lee N, Tap WD, Gounder MM, D'Angelo SP, Saltz L, Stadler ZK, Scher HI, Baselga J, Razavi P, Klebanoff CA, Yaeger R, Segal NH, Ku GY, DeMatteo RP, Ladanyi M, Rizvi NA, Berger MF, Riaz N, Solit DB, Chan TA, Morris LGT (2019) Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51:202–206. https://doi.org/10.1038/s41588-018-0312-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kazdal D, Endris V, Allgäuer M, Kriegsmann M, Leichsenring J, Volckmar AL, Harms A, Kirchner M, Kriegsmann K, Neumann O, Brandt R, Talla SB, Rempel E, Ploeger C, von Winterfeld M, Christopoulos P, Merino DM, Stewart M, Allen J, Bischoff H, Meister M, Muley T, Herth F, Penzel R, Warth A, Winter H, Fröhling S, Peters S, Swanton C, Thomas M, Schirmacher P, Budczies J, Stenzinger A (2019) Spatial and temporal heterogeneity of panel-based tumor mutational burden in pulmonary adenocarcinoma: separating biology from technical artifacts. J Thorac Oncol 14:1935–1947. https://doi.org/10.1016/j.jtho.2019.07.006

    Article  CAS  PubMed  Google Scholar 

  69. Fenizia F, Pasquale R, Roma C, Bergantino F, Iannaccone A, Normanno N (2018) Measuring tumor mutation burden in non-small cell lung cancer: tissue versus liquid biopsy. Transl Lung Cancer Res 7:668–677. https://doi.org/10.21037/tlcr.2018.09.23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS (2018) 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. https://doi.org/10.1038/s41591-018-0134-3

    Article  CAS  PubMed  Google Scholar 

  71. Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S (2020) Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol 6:661–674. https://doi.org/10.1001/jamaoncol.2020.0237

    Article  PubMed  PubMed Central  Google Scholar 

  72. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36:633–641. https://doi.org/10.1200/jco.2017.75.3384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, Schrock AB, Hartmaier RJ, Trabucco SE, Gay L, Ali SM, Elvin JA, Singal G, Ross JS, Fabrizio D, Szabo PM, Chang H, Sasson A, Srinivasan S, Kirov S, Szustakowski J, Vitazka P, Edwards R, Bufill JA, Sharma N, Ou SI, Peled N, Spigel DR, Rizvi H, Aguilar EJ, Carter BW, Erasmus J, Halpenny DF, Plodkowski AJ, Long NM, Nishino M, Denning WL, Galan-Cobo A, Hamdi H, Hirz T, Tong P, Wang J, Rodriguez-Canales J, Villalobos PA, Parra ER, Kalhor N, Sholl LM, Sauter JL, Jungbluth AA, Mino-Kenudson M, Azimi R, Elamin YY, Zhang J, Leonardi GC, Jiang F, Wong KK, Lee JJ, Papadimitrakopoulou VA, Wistuba II, Miller VA, Frampton GM, Wolchok JD, Shaw AT, Jänne PA, Stephens PJ, Rudin CM, Geese WJ, Albacker LA, Heymach JV (2018) STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822–835. https://doi.org/10.1158/2159-8290.Cd-18-0099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rizvi N, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn M, Papadimitrakopoulou V, Heymach J, Scheuring U, Higgs B, Ye J, Kuziora M, Wu S, Liu F, Si H, Peters S (2019) Mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC Trial. J Thorac Oncol 14:S217

    Article  Google Scholar 

  75. Schoenfeld AJ, Bandlamudi C, Lavery JA, Montecalvo J, Namakydoust A, Rizvi H, Egger J, Concepcion CP, Paul S, Arcila ME, Daneshbod Y, Chang J, Sauter JL, Beras A, Ladanyi M, Jacks T, Rudin CM, Taylor BS, Donoghue MTA, Heller G, Hellmann MD, Rekhtman N, Riely GJ (2020) The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer. Clin Cancer Res 26:5701–5708. https://doi.org/10.1158/1078-0432.Ccr-20-1825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 Study. J Clin Oncol 38:1–10. https://doi.org/10.1200/jco.19.02105

    Article  CAS  PubMed  Google Scholar 

  77. Administration USFaD (2017) https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumabfirst-tissuesite-agnostic-indication. Accessed 23 Jan 2021

  78. Schrock A, Sharma N, Peled N, Bufill J, Srkalovic G, Spigel D, Fabrizio D, Frampton G, Connelly C, BethLipka M, Belilovski A, Lo J, Li Y, Sun J, Gowen K, Kalemkerian G, Raez L, Ou S, Ross J, Stephens P, Ali S, Miller V (2017) Updated dataset assessing tumor mutation burden (TMB) as a biomarker for response to PD-1/PD-L1 targeted therapies in lung cancer (LC). J Thorac Oncol 12:S422

    Article  Google Scholar 

  79. Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J (2018) Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 7:746–756. https://doi.org/10.1002/cam4.1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541:321–330. https://doi.org/10.1038/nature21349

    Article  CAS  PubMed  Google Scholar 

  81. Guo X, Zhang Y, Zheng L, Zheng C, Song J, Zhang Q, Kang B, Liu Z, Jin L, Xing R, Gao R, Zhang L, Dong M, Hu X, Ren X, Kirchhoff D, Roider HG, Yan T, Zhang Z (2018) Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med 24:978–985. https://doi.org/10.1038/s41591-018-0045-3

    Article  CAS  PubMed  Google Scholar 

  82. Hamm CA, Pry K, Lu J, Bacus S (2019) Immune profiling reveals the diverse nature of the immune response in NSCLC and reveals signaling pathways that may influence the anti-tumor immune response. Exp Mol Pathol 109:1–15. https://doi.org/10.1016/j.yexmp.2019.04.004

    Article  CAS  PubMed  Google Scholar 

  83. Taube JM, Akturk G, Angelo M, Engle EL, Gnjatic S, Greenbaum S, Greenwald NF, Hedvat CV, Hollmann TJ, Juco J, Parra ER, Rebelatto MC, Rimm DL, Rodriguez-Canales J, Schalper KA, Stack EC, Ferreira CS, Korski K, Lako A, Rodig SJ, Schenck E, Steele KE, Surace MJ, Tetzlaff MT, von Loga K, Wistuba II, Bifulco CB (2020) The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation. J Immunother Cancer 8:e000155. https://doi.org/10.1136/jitc-2019-000155

    Article  PubMed  PubMed Central  Google Scholar 

  84. Rosenbaum M, Khosrowjerdi S, Kamesan V, Digumarthy S, Gainor J, Mino-Kenudson M (2018) The utility of PD-L1/CD8 dual immunohistochemistry for prediction of response to immunotherapy in non-small cell lung cancer (NSCLC). J Thorac Oncol 13:S533

    Article  Google Scholar 

  85. Fumet JD, Richard C, Ledys F, Klopfenstein Q, Joubert P, Routy B, Truntzer C, Gagné A, Hamel MA, Guimaraes CF, Coudert B, Arnould L, Favier L, Lagrange A, Ladoire S, Saintigny P, Ortiz-Cuaran S, Perol M, Foucher P, Hofman P, Ilie M, Chevrier S, Boidot R, Derangere V, Ghiringhelli F (2018) Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy. Br J Cancer 119:950–960. https://doi.org/10.1038/s41416-018-0220-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hurkmans DP, Kuipers ME, Smit J, van Marion R, Mathijssen RHJ, Postmus PE, Hiemstra PS, Aerts J, von der Thüsen JH, van der Burg SH (2020) Tumor mutational load, CD8(+) T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients. Cancer Immunol Immunother 69:771–777. https://doi.org/10.1007/s00262-020-02506-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gettinger SN, Choi J, Mani N, Sanmamed MF, Datar I, Sowell R, Du VY, Kaftan E, Goldberg S, Dong W, Zelterman D, Politi K, Kavathas P, Kaech S, Yu X, Zhao H, Schlessinger J, Lifton R, Rimm DL, Chen L, Herbst RS, Schalper KA (2018) A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat Commun 9:3196. https://doi.org/10.1038/s41467-018-05032-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Toranomon Hospital, Tokyo, Japan

    Hironori Uruga

  2. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Warren 122, Boston, MA, 02114, USA

    Mari Mino-Kenudson

Authors
  1. Hironori Uruga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mari Mino-Kenudson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Hironori Uruga: writing—original draft—lead

Mari Mino-Kenudson: writing—review and editing—lead

Corresponding author

Correspondence to Mari Mino-Kenudson.

Ethics declarations

We toed the ethical standards of the institutional with the 1964 Helsinki declaration.

Conflict of interest

H. Uruga declares no conflicts of interest associated with this manuscript. M. Mino-Kenudson has served as a compensated consultant for H3 Biomedicine and AstraZeneca and has received research (institutional) funding from Novartis, all of which are not related to this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uruga, H., Mino-Kenudson, M. Predictive biomarkers for response to immune checkpoint inhibitors in lung cancer: PD-L1 and beyond. Virchows Arch 478, 31–44 (2021). https://doi.org/10.1007/s00428-021-03030-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-021-03030-8

Keywords

Search

Navigation