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Potential biomarkers for immunotherapy in non-small-cell lung cancer

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Abstract

For individuals with advanced or metastatic non-small cell lung cancer (NSCLC), the primary treatment is platinum-based doublet chemotherapy. Immune checkpoint inhibitors (ICIs), primarily PD-1/PD-L1 and CTLA-4, have been found to be effective in patients with NSCLC who have no EGFR/ALK mutations. Furthermore, ICIs are considered a standard therapy. The quantity of fresh immunogenic antigens discovered by cytotoxic T cells was measured by PD-L1 expression and tumor mutational burden (TMB), which were the first biomarkers assessed in clinical trials. However, immunotherapy did not have response efficacy markers similar to targeted therapy, highlighting the significance of newly developed biomarkers. This investigation aims to review the research on immunotherapy for NSCLC, focusing primarily on the impact of biomarkers on efficacy prediction to determine whether biomarkers may be utilized to evaluate the effectiveness of immunotherapy.

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References

  1. Osmani, L., Askin, F., Gabrielson, E., et al. (2018). Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy[J]. Seminars in Cancer Biology, 52(Pt 1), 103–109.

    Article  CAS  PubMed  Google Scholar 

  2. Arbour, K. C., & Riely, G. J. (2019). Systemic therapy for locally advanced and metastatic non-small cell lung cancer: A review[J]. JAMA, 322(8), 764–774.

    Article  CAS  PubMed  Google Scholar 

  3. Camidge, D. R., Doebele, R. C., & Kerr, K. M. (2019). Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC[J]. Nature Reviews. Clinical Oncology, 16(6), 341–355.

    Article  CAS  PubMed  Google Scholar 

  4. Reck, M., Rodríguez-Abreu, D., Robinson, A. G., et al. (2016). Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer[J]. New England Journal of Medicine, 375(19), 1823–1833.

    Article  CAS  PubMed  Google Scholar 

  5. Gandhi, L., Rodriguez-Abreu, D., Gadgeel, S., et al. (2018). Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer[J]. New England Journal of Medicine, 378(22), 2078–2092.

    Article  CAS  PubMed  Google Scholar 

  6. Borghaei, H., Paz-Ares, L., Horn, L., et al. (2015). Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. New England Journal of Medicine, 373(17), 1627–1639.

    Article  CAS  PubMed  Google Scholar 

  7. Rittmeyer, A., Barlesi, F., Waterkamp, D., et al. (2017). Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial[J]. The Lancet, 389(10066), 255–265.

    Article  Google Scholar 

  8. Powles, T., Durán, I., Van Der Heijden, M. S., et al. (2018). Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial[J]. The Lancet, 391(10122), 748–757.

    Article  CAS  Google Scholar 

  9. Patel, M. R., Ellerton, J., Infante, J. R., et al. (2018). Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): Pooled results from two expansion cohorts of an open-label, phase 1 trial[J]. The Lancet Oncology, 19(1), 51–64.

    Article  CAS  PubMed  Google Scholar 

  10. Sharma, P., Retz, M., Siefker-Radtke, A., et al. (2017). Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial[J]. The Lancet Oncology, 18(3), 312–322.

    Article  CAS  PubMed  Google Scholar 

  11. Powles, T., O’donnell, P. H., Massard, C., et al. (2017). Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma[J]. JAMA Oncology, 3(9): e172411.

  12. Chung, H. C., Ros, W., Delord, J.-P., et al. (2019). Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: Results from the phase II KEYNOTE-158 study[J]. Journal of Clinical Oncology, 37(17), 1470–1478.

    Article  CAS  PubMed  Google Scholar 

  13. Schmid, P., Adams, S., Rugo, H. S., et al. (2018). Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer[J]. New England Journal of Medicine, 379(22), 2108–2121.

    Article  CAS  PubMed  Google Scholar 

  14. Le, D. T., Uram, J. N., Wang, H., et al. (2015). PD-1 blockade in tumors with mismatch-repair deficiency[J]. New England Journal of Medicine, 372(26), 2509–2520.

    Article  CAS  PubMed  Google Scholar 

  15. Arrieta, O., Barron, F., Ramirez-Tirado, L. A., et al. (2020). Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced non-small cell lung cancer: The PROLUNG phase 2 randomized clinical trial[J]. JAMA Oncology, 6(6), 856–864.

    Article  PubMed  Google Scholar 

  16. Fuchs, C. S., Doi, T., Jang, R. W., et al. (2018). Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer[J]. JAMA Oncology, 4(5), e180013.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Motzer, R. J., Escudier, B., Mcdermott, D. F., et al. (2015). Nivolumab versus everolimus in advanced renal-cell carcinoma[J]. New England Journal of Medicine, 373(19), 1803–1813.

    Article  CAS  PubMed  Google Scholar 

  18. El-Khoueiry, A. B., Sangro, B., Yau, T., et al. (2017). Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. The Lancet, 389(10088), 2492–2502.

    Article  CAS  Google Scholar 

  19. Zhu, A. X., Finn, R. S., Edeline, J., et al. (2018). Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial[J]. The Lancet Oncology, 19(7), 940–952.

    Article  PubMed  Google Scholar 

  20. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al. (2015). Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J]. New England Journal of Medicine, 373(1), 23–34.

    Article  PubMed  Google Scholar 

  21. Antonia, S. J., Villegas, A., Daniel, D., et al. (2017). Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer[J]. New England Journal of Medicine, 377(20), 1919–1929.

    Article  CAS  PubMed  Google Scholar 

  22. Di Matteo, B., Ranieri, R., Manca, A., et al. (2021). Cell-based therapies for the treatment of shoulder and elbow tendinopathies: A scoping review[J]. Stem Cells Int, 2021, 1–12.

    Article  CAS  Google Scholar 

  23. Simonsen, A. T., Utke, A., Lade-Keller, J., et al. (2022). A targeted expression panel for classification, gene fusion detection and PD-L1 measurements—can molecular profiling replace immunohistochemistry in non-small cell lung cancer?[J]. Experimental and Molecular Pathology, 125, 104749.

    Article  CAS  PubMed  Google Scholar 

  24. Gun, S. Y., Lee, S. W. L., Sieow, J. L., et al. (2019). Targeting immune cells for cancer therapy[J]. Redox Biology, 25, 101174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Montano-Samaniego, M., Bravo-Estupinan, D. M., Mendez-Guerrero, O., et al. (2020). Strategies for targeting gene therapy in cancer cells with tumor-specific promoters[J]. Frontiers in Oncology, 10, 605380.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Strickler, J. H., Hanks, B. A., & Khasraw, M. (2021). Tumor mutational burden as a predictor of immunotherapy response: Is more always better?[J]. Clinical Cancer Research, 27(5), 1236–1241.

    Article  CAS  PubMed  Google Scholar 

  27. Mcgrail, D. J., Pilié, P. G., Rashid, N. U., et al. (2021). High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types[J]. Annals of Oncology, 32(5), 661–672.

    Article  CAS  PubMed  Google Scholar 

  28. Palmeri, M., Mehnert, J., Silk, A. W., et al. (2022). Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers[J]. ESMO Open, 7(1), 100336.

    Article  CAS  PubMed  Google Scholar 

  29. Vrankar M, Kern I, Stanic K. (2020). Prognostic value of PD-L1 expression in patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy. Radiation Oncology, 15(1):247.

  30. Kao, C., Powers, E., Wu, Y., et al. (2021). Predictive value of combining biomarkers for clinical outcomes in advanced non-small cell lung cancer patients receiving immune checkpoint inhibitors[J]. Clinical Lung Cancer, 22(6), 500–509.

    Article  CAS  PubMed  Google Scholar 

  31. Hinterleitner, C., Strähle, J., Malenke, E., et al. (2021). Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer[J]. Nature Communications, 12(1):7005.

  32. Prasad, V., & Addeo, A. (2020). The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: Was it a wise decision? No[J]. Annals of Oncology, 31(9), 1112–1114.

    Article  CAS  PubMed  Google Scholar 

  33. Tsao, M. S., Kerr, K. M., Kockx, M., et al. (2018). PD-L1 Immunohistochemistry comparability study in real-life clinical samples: Results of blueprint phase 2 project[J]. Journal of Thoracic Oncology, 13(9), 1302–1311.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Thierry, A. R., El Messaoudi, S., Gahan, P. B., et al. (2016). Origins, structures, and functions of circulating DNA in oncology[J]. Cancer and Metastasis Reviews, 35(3), 347–376.

    Article  CAS  PubMed  Google Scholar 

  35. Diehl, F., Schmidt, K., Choti, M. A., et al. (2008). Circulating mutant DNA to assess tumor dynamics[J]. Nature Medicine, 14(9), 985–990.

    Article  CAS  PubMed  Google Scholar 

  36. Parikh, A. R., Van Seventer, E. E., Siravegna, G., et al. (2021). Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer[J]. Clinical Cancer Research, 27(20), 5586–5594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Adalsteinsson, V. A., Ha, G., Freeman, S. S., et al. (2017). Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors[J]. Nature Communications, 8(1), 1324.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Garon, E. B., Rizvi, N. A., Hui, R., et al. (2015). Pembrolizumab for the treatment of non-small-cell lung cancer[J]. New England Journal of Medicine, 372(21), 2018–2028.

    Article  PubMed  Google Scholar 

  39. Brahmer, J., Reckamp, K. L., Baas, P., et al. (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J]. New England Journal of Medicine, 373(2), 123–135.

    Article  CAS  PubMed  Google Scholar 

  40. Rizvi, N. A., Mazières, J., Planchard, D., et al. (2015). Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial[J]. The Lancet Oncology, 16(3), 257–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou, F., Qiao, M., & Zhou, C. (2021). The cutting-edge progress of immune-checkpoint blockade in lung cancer[J]. Cellular & Molecular Immunology, 18(2), 279–293.

    Article  CAS  Google Scholar 

  42. Gettinger, S., Rizvi, N. A., Chow, L. Q., et al. (2016). Nivolumab monotherapy for first-line treatment of advanced non–small-cell lung cancer[J]. Journal of Clinical Oncology, 34(25), 2980–2987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kanda, S., Goto, K., Shiraishi, H., et al. (2016). Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: A four arms phase Ib study[J]. Annals of Oncology, 27(12), 2242–2250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gettinger, S., Horn, L., Jackman, D., et al. (2018). Five-year follow-up of nivolumab in previously treated advanced non–small-cell lung cancer: Results from the CA209-003 study[J]. Journal of Clinical Oncology, 36(17), 1675–1684.

    Article  CAS  PubMed  Google Scholar 

  45. Travert, C., Barlesi, F., Greillier, L., et al. (2020). Immune oncology biomarkers in lung cancer: An overview[J]. Current Oncology Reports, 22(11), 107.

    Article  PubMed  Google Scholar 

  46. Brozos-Vazquez, E. M., Diaz-Pena, R., Garcia-Gonzalez, J., et al. (2021). Immunotherapy in nonsmall-cell lung cancer: Current status and future prospects for liquid biopsy[J]. Cancer Immunology, Immunotherapy, 70(5), 1177–1188.

    Article  PubMed  Google Scholar 

  47. Forde, P. M., Chaft, J. E., Smith, K. N., et al. (2018). Neoadjuvant PD-1 blockade in resectable lung cancer[J]. New England Journal of Medicine, 378(21), 1976–1986.

    Article  CAS  PubMed  Google Scholar 

  48. Goldberg, S. B., Gettinger, S. N., Mahajan, A., et al. (2016). Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: Early analysis of a non-randomised, open-label, phase 2 trial[J]. The Lancet Oncology, 17(7), 976–983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nishio, M., Takahashi, T., Yoshioka, H., et al. (2019). KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer[J]. Cancer Science, 110(3), 1012–1020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Reck, M., Rodríguez-Abreu, D., Robinson, A. G., et al. (2021). Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non–small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%[J]. Journal of Clinical Oncology, 39(21), 2339–2349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Horn, L., Gettinger, S. N., Gordon, M. S., et al. (2018). Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: Final results from a phase I study[J]. European Journal of Cancer, 101, 201–209.

    Article  CAS  PubMed  Google Scholar 

  52. Kowanetz, M., Zou, W., Gettinger, S. N., et al. (2018). Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)[J]. Proceedings of the National Academy of Sciences of the United States of America, 115(43), E10119–E10126.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Althammer, S., Tan, T. H., Spitzmuller, A., et al. (2019). Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy[J]. Journal for Immunotherapy of Cancer, 7(1), 121.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hellmann, M. D., Rizvi, N. A., Goldman, J. W., et al. (2017). Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): Results of an open-label, phase 1, multicohort study[J]. The Lancet Oncology, 18(1), 31–41.

    Article  CAS  PubMed  Google Scholar 

  55. Ready, N., Hellmann, M. D., Awad, M. M., et al. (2019). First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers[J]. Journal of Clinical Oncology, 37(12), 992–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Socinski, M. A., Jotte, R. M., Cappuzzo, F., et al. (2018). Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J]. New England Journal of Medicine, 378(24), 2288–2301.

    Article  CAS  PubMed  Google Scholar 

  57. Besse, B., Garrido, P., Cortot, A. B., et al. (2020). Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer[J]. Lung Cancer, 142, 63–69.

    Article  PubMed  Google Scholar 

  58. Rizzo, A., & Ricci, A. D. (2022). PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: How can they assist drug clinical trials?[J]. Expert Opinion on Investigational Drugs, 31(4), 415–423.

    Article  CAS  PubMed  Google Scholar 

  59. Marabelle, A., Fakih, M., Lopez, J., et al. (2020). Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study[J]. The lancet Oncology, 21(10), 1353–1365.

    Article  CAS  PubMed  Google Scholar 

  60. Hellmann, M. D., Ciuleanu, T. E., Pluzanski, A., et al. (2018). Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J]. New England Journal of Medicine, 378(22), 2093–2104.

    Article  CAS  PubMed  Google Scholar 

  61. Si, H., Kuziora, M., Quinn, K. J., et al. (2021). A blood-based assay for assessment of tumor mutational burden in first-line metastatic NSCLC treatment: Results from the MYSTIC study[J]. Clinical Cancer Research, 27(6), 1631–1640.

    Article  CAS  PubMed  Google Scholar 

  62. Jiang, H., Zheng, Y., Qian, J., et al. (2021). Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: Two cohorts of an open-label, phase 1b study[J]. Cancer Immunology, Immunotherapy, 70(3), 857–868.

    Article  CAS  PubMed  Google Scholar 

  63. Chakrabarti, S., Peterson, C. Y., Sriram, D., et al. (2020). Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions[J]. World J Gastrointest Oncol, 12(8), 808–832.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Abbosh, C., Birkbak, N. J., & Swanton, C. (2018). Early stage NSCLC—challenges to implementing ctDNA-based screening and MRD detection[J]. Nature Reviews. Clinical Oncology, 15(9), 577–586.

    Article  CAS  PubMed  Google Scholar 

  65. Peng, Y., Mei, W., Ma, K., et al. (2021). Circulating tumor DNA and minimal residual disease (MRD) in solid tumors: Current horizons and future perspectives[J]. Frontiers in Oncology, 11, 763790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., et al. (2017). Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling[J]. Cancer Discovery, 7(12), 1394–1403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chabon, J. J., Hamilton, E. G., Kurtz, D. M., et al. (2020). Integrating genomic features for non-invasive early lung cancer detection[J]. Nature, 580(7802), 245–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Reinert, T., Henriksen, T. V., Christensen, E., et al. (2019). Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer[J]. JAMA Oncology, 5(8), 1124–1131.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Tie, J., Wang, Y., Tomasetti, C., et al. (2016). Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer[J]. Science Translational Medicine, 8(346), 346ra92.

  70. Tie, J., Cohen, J. D., Wang, Y., et al. (2019). Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer[J]. JAMA Oncology, 5(12), 1710–1717.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Anandappa, G., Starling, N., Begum, R., et al. (2021). Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC)[J]. Journal of Clinical Oncology, 39(3_suppl), 102–102.

  72. Hofman, P., Heeke, S., Alix-Panabieres, C., et al. (2019). Liquid biopsy in the era of immuno-oncology: Is it ready for prime-time use for cancer patients?[J]. Annals of Oncology, 30(9), 1448–1459.

    Article  CAS  PubMed  Google Scholar 

  73. Le, D. T., Durham, J. N., Smith, K. N., et al. (2017). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 357(6349), 409–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lu, C., Guan, J., Lu, S., et al. (2021). DNA Sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity[J]. Cancer Cell, 39(1), 96–108 e6.

  75. Wang, Z., Duan, J., Cai, S., et al. (2019). Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel[J]. JAMA Oncology, 5(5), 696–702.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Snyder, A., Morrissey, M. P., & Hellmann, M. D. (2019). Use of circulating tumor DNA for cancer immunotherapy[J]. Clinical Cancer Research, 25(23), 6909–6915.

    Article  CAS  PubMed  Google Scholar 

  77. Georgiadis, A., Durham, J. N., Keefer, L. A., et al. (2019). Noninvasive detection of microsatellite instability and high tumor mutation burden in cancer patients treated with PD-1 blockade[J]. Clinical Cancer Research, 25(23), 7024–7034.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Willis, J., Lefterova, M. I., Artyomenko, A., et al. (2019). Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel[J]. Clinical Cancer Research, 25(23), 7035–7045.

    Article  CAS  PubMed  Google Scholar 

  79. Goodman, A. M., Sokol, E. S., Frampton, G. M., et al. (2019). Microsatellite-stable tumors with high mutational burden benefit from immunotherapy[J]. Cancer Immunology Research, 7(10), 1570–1573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gandara, D. R., Paul, S. M., Kowanetz, M., et al. (2018). Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab[J]. Nature Medicine, 24(9), 1441–1448.

    Article  CAS  PubMed  Google Scholar 

  81. Leal, A., Van Grieken, N. C. T., Palsgrove, D. N., et al. (2020). White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer[J]. Nature Communications, 11(1), 525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Moding, E. J., Liu, Y., Nabet, B. Y., et al. (2020). Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small cell lung cancer[J]. Nat Cancer, 1(2), 176–183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Anagnostou, V., Forde, P. M., White, J. R., et al. (2019). Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer[J]. Cancer Research, 79(6), 1214–1225.

    Article  CAS  PubMed  Google Scholar 

  84. Nabet, B. Y., Esfahani, M. S., Moding, E. J., et al. (2020). Noninvasive early identification of therapeutic benefit from immune checkpoint inhibition[J]. Cell, 183(2), 363–376 e13.

  85. Wu, T. D., Madireddi, S., De Almeida, P. E., et al. (2020). Peripheral T cell expansion predicts tumour infiltration and clinical response[J]. Nature, 579(7798), 274–278.

    Article  CAS  PubMed  Google Scholar 

  86. Pantel, K., & Hayes, D. F. (2018). Disseminated breast tumour cells: Biological and clinical meaning[J]. Nature Reviews. Clinical Oncology, 15(3), 129–131.

    Article  PubMed  Google Scholar 

  87. Ilie, M., Long-Mira, E., Bence, C., et al. (2016). Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: A potential issue for anti-PD-L1 therapeutic strategies[J]. Annals of Oncology, 27(1), 147–153.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, Y., Dong, Z., Jiang, T., et al. (2018). Heterogeneity of PD-L1 Expression among the different histological components and metastatic lymph nodes in patients with resected lung adenosquamous carcinoma[J]. Clinical Lung Cancer, 19(4), e421–e430.

    Article  CAS  Google Scholar 

  89. Goodman, A. M., Kato, S., Bazhenova, L., et al. (2017). Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers[J]. Molecular Cancer Therapeutics, 16(11), 2598–2608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Samstein, R. M., Lee, C. H., Shoushtari, A. N., et al. (2019). Tumor mutational load predicts survival after immunotherapy across multiple cancer types[J]. Nature Genetics, 51(2), 202–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Danilova, L., Wang, H., Sunshine, J., et al. (2016). Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors[J]. Proceedings of the National Academy of Sciences of the United States of America, 113(48), E7769-e7777.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Rizvi, N. A., Hellmann, M. D., Snyder, A., et al. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science, 348(6230), 124–8.

  93. Dhar, M., Wong, J., Che, J., et al. (2018). Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer[J]. Science and Reports, 8(1), 2592.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  95. Kallergi, G., Vetsika, E. K., Aggouraki, D., et al. (2018). Evaluation of PD-L1/PD-1 on circulating tumor cells in patients with advanced non-small cell lung cancer[J]. Ther Adv Med Oncol, 10, 1758834017750121.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Nicolazzo, C., Raimondi, C., Mancini, M., et al. (2016). Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab[J]. Science and Reports, 6, 31726.

    Article  CAS  Google Scholar 

  97. Anantharaman, A., Friedlander, T., Lu, D., et al. (2016). Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) in muscle invasive and metastatic bladder cancer patients[J]. BMC Cancer, 16(1), 744.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Mazel, M., Jacot, W., Pantel, K., et al. (2015). Frequent expression of PD-L1 on circulating breast cancer cells[J]. Molecular Oncology, 9(9), 1773–1782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yue, C., Jiang, Y., Li, P., et al. (2018). Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy[J]. Oncoimmunology, 7(7), e1438111.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lu, C., Zhang, Y. C., Chen, Z. H., et al. (2022). Applications of circulating tumor DNA in immune checkpoint inhibition: Emerging roles and future perspectives[J]. Frontiers in Oncology, 12, 836891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Roosan, M. R., Mambetsariev, I., Pharaon, R., et al. (2021). Usefulness of circulating tumor DNA in identifying somatic mutations and tracking tumor evolution in patients with non-small cell lung cancer[J]. Chest, 160(3), 1095–1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, E., Feldman, R., Wistuba, Ii. (2018). Update on EGFR mutational testing and the potential of noninvasive liquid biopsy in non-small-cell lung cancer[J]. Clin Lung Cancer, 19(2), 105–114.

  103. Cabel, L., Proudhon, C., Romano, E., et al. (2018). Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy[J]. Nature Reviews. Clinical Oncology, 15(10), 639–650.

    Article  CAS  PubMed  Google Scholar 

  104. Lipson, E. J., Velculescu, V. E., Pritchard, T. S., et al. (2014). Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade[J]. Journal for Immunotherapy of Cancer, 2(1), 42.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ibrahim, A. E., Arends, M. J., Silva, A. L., et al. (2011). Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression[J]. Gut, 60(4), 499–508.

    Article  CAS  PubMed  Google Scholar 

  106. Gray, E. S., Rizos, H., Reid, A. L., et al. (2015). Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma[J]. Oncotarget, 6(39), 42008–42018.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Lee, J. H., Long, G. V., Boyd, S., et al. (2017). Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma[J]. Annals of Oncology, 28(5), 1130–1136.

    Article  CAS  PubMed  Google Scholar 

  108. Irizarry, R. A., Ladd-Acosta, C., Wen, B., et al. (2009). The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores[J]. Nature Genetics, 41(2), 178–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Feinberg, A. P., & Vogelstein, B. (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts[J]. Nature, 301(5895), 89–92.

    Article  CAS  PubMed  Google Scholar 

  110. Greger, V., Passarge, E., Höpping, W., et al. (1989). Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma[J]. Human Genetics, 83(2), 155–158.

    Article  CAS  PubMed  Google Scholar 

  111. Sakai, T., Toguchida, J., Ohtani, N., et al. (1991). Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene[J]. American Journal of Human Genetics, 48(5), 880–888.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Herman, J. G., Latif, F., Weng, Y., et al. (1994). Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma[J]. Proceedings of the National Academy of Sciences of the United States of America, 91(21), 9700–9704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Merlo, A., Herman, J. G., Mao, L., et al. (1995). 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers[J]. Nature Medicine, 1(7), 686–692.

    Article  CAS  PubMed  Google Scholar 

  114. Herman, J. G., Merlo, A., Mao, L., et al. (1995). Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers[J]. Cancer Research, 55(20), 4525–4530.

    CAS  PubMed  Google Scholar 

  115. Gonzalez-Zulueta, M., Bender, C. M., Yang, A. S., et al. (1995). Methylation of the 5’ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing[J]. Cancer Research, 55(20), 4531–4535.

    CAS  PubMed  Google Scholar 

  116. Esteller, M. (2008). Epigenetics in cancer[J]. New England Journal of Medicine, 358(11), 1148–1159.

    Article  CAS  PubMed  Google Scholar 

  117. Xu, R. H., Wei, W., Krawczyk, M., et al. (2017). Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma[J]. Nature Materials, 16(11), 1155–1161.

    Article  CAS  PubMed  Google Scholar 

  118. Baylin, S. B., Jones, P. A. (2016). Epigenetic determinants of cancer[J]. Cold Spring Harbor Perspectives in Biology, 8(9).

  119. Baylin, S. B., & Jones, P. A. (2011). A decade of exploring the cancer epigenome—biological and translational implications[J]. Nature Reviews Cancer, 11(10), 726–734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Board, R. E., Knight, L., Greystoke, A., et al. (2008). DNA methylation in circulating tumour DNA as a biomarker for cancer[J]. Biomark Insights, 2, 307–319.

    PubMed  PubMed Central  Google Scholar 

  121. Amatu, A., Barault, L., Moutinho, C., et al. (2016). Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer[J]. Annals of Oncology, 27(6), 1062–1067.

    Article  CAS  PubMed  Google Scholar 

  122. Brock, M. V., Hooker, C. M., Ota-Machida, E., et al. (2008). DNA methylation markers and early recurrence in stage I lung cancer[J]. New England Journal of Medicine, 358(11), 1118–1128.

    Article  CAS  PubMed  Google Scholar 

  123. Niklasson, B., & Vene, S. (1996). Vector-borne viral diseases in Sweden—a short review[J]. Archives of Virology. Supplementum, 11, 49–55.

    CAS  PubMed  Google Scholar 

  124. Ramirez, J. L., Rosell, R., Taron, M., et al. (2005). 14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group[J]. Journal of Clinical Oncology, 23(36), 9105–9112.

    Article  CAS  PubMed  Google Scholar 

  125. Shipony, Z., Mukamel, Z., Cohen, N. M., et al. (2014). Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells[J]. Nature, 513(7516), 115–119.

    Article  CAS  PubMed  Google Scholar 

  126. Xu. G. L., Bestor, T. H., Bourc’his. D., et al. (1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene[J]. Nature, 402(6758), 187–91.

  127. Balgkouranidou, I., Chimonidou, M., Milaki, G., et al. (2016). SOX17 promoter methylation in plasma circulating tumor DNA of patients with non-small cell lung cancer[J]. Clinical Chemistry and Laboratory Medicine, 54(8), 1385–1393.

    Article  CAS  PubMed  Google Scholar 

  128. Guo, D., Yang, L., Yang, J., et al. (2020). Plasma cell-free DNA methylation combined with tumor mutation detection in prognostic prediction of patients with non-small cell lung cancer (NSCLC)[J]. Medicine (Baltimore), 99(26), e20431.

    Article  CAS  PubMed  Google Scholar 

  129. Peng, X., Liu, X., Xu, L., et al. (2019). The mSHOX2 is capable of assessing the therapeutic effect and predicting the prognosis of stage IV lung cancer[J]. Journal of Thoracic Disease, 11(6), 2458–2469.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Powrózek, T., Krawczyk, P., Nicoś, M., et al. (2016). Methylation of the DCLK1 promoter region in circulating free DNA and its prognostic value in lung cancer patients[J]. Clinical and Translational Oncology, 18(4), 398–404.

    Article  PubMed  Google Scholar 

  131. Schmidt, B., Beyer, J., Dietrich, D., et al. (2015). Quantification of cell-free mSHOX2 Plasma DNA for therapy monitoring in advanced stage non-small cell (NSCLC) and small-cell lung cancer (SCLC) patients[J]. PLoS ONE, 10(2), e0118195.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Vinayanuwattikun, C., Sriuranpong, V., Tanasanvimon, S., et al. (2011). Epithelial-specific methylation marker: A potential plasma biomarker in advanced non-small cell lung cancer[J]. Journal of Thoracic Oncology, 6(11), 1818–1825.

    Article  PubMed  Google Scholar 

  133. Duruisseaux, M., Martínez-Cardús, A., Calleja-Cervantes, M. E., et al. (2018). Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: A multicentre, retrospective analysis[J]. The Lancet Respiratory Medicine, 6(10), 771–781.

    Article  CAS  PubMed  Google Scholar 

  134. Cho, J. W., Hong, M. H., Ha, S. J., et al. (2020). Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer[J]. Experimental & Molecular Medicine, 52(9), 1550–1563.

    Article  CAS  Google Scholar 

  135. Luo, R., Song, J., Xiao, X., et al. (2020). Identifying CpG methylation signature as a promising biomarker for recurrence and immunotherapy in non-small-cell lung carcinoma[J]. Aging (Albany NY), 12(14), 14649–14676.

    Article  CAS  PubMed  Google Scholar 

  136. Shang, S., Li, X., Gao, Y., et al. (2021). MeImmS: Predict clinical benefit of anti-PD-1/PD-L1 treatments based on DNA methylation in non-small cell lung cancer[J]. Frontiers in Genetics, 12, 676449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Guerreiro, I. M., Barros-Silva, D., Lopes, P., et al. (2020). RAD51B(me) Levels as a potential predictive biomarker for PD-1 blockade response in non-small cell lung cancer[J]. Journal of Clinical Medicine, 9(4).

  138. Galvano, A., Gristina, V., Malapelle, U., et al. (2021). The prognostic impact of tumor mutational burden (TMB) in the first-line management of advanced non-oncogene addicted non-small-cell lung cancer (NSCLC): A systematic review and meta-analysis of randomized controlled trials[J]. ESMO Open, 6(3), 100124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Addeo, A., Friedlaender, A., Banna, G. L., et al. (2021). TMB or not TMB as a biomarker: That is the question[J]. Critical Reviews in Oncology Hematology, 163, 103374.

    Article  PubMed  Google Scholar 

  140. Tian, Y., Xu, J., Chu, Q., et al. (2020). A novel tumor mutational burden estimation model as a predictive and prognostic biomarker in NSCLC patients[J]. BMC Medicine, 18(1), 232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sholl, L. M., Hirsch, F. R., Hwang, D., et al. (2020). The promises and challenges of tumor mutation burden as an immunotherapy biomarker: A perspective from the international association for the study of lung cancer pathology committee[J]. Journal of Thoracic Oncology, 15(9), 1409–1424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cai, L., Bai, H., Duan, J., et al. (2019). Epigenetic alterations are associated with tumor mutation burden in non-small cell lung cancer[J]. Journal for Immunotherapy of Cancer, 7(1), 198.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Dong, A., Zhao, Y., Li, Z., et al. (2021). PD-L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non-small cell lung cancer?[J]. The Journal of Gene Medicine, 23(2), e3294.

    Article  CAS  PubMed  Google Scholar 

  144. Mosele, F., Remon, J., Mateo, J., et al. (2020). Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group[J]. Annals of Oncology, 31(11), 1491–1505.

    Article  CAS  PubMed  Google Scholar 

  145. Oliver, J., Garcia-Aranda, M., Chaves, P., et al. (2022). Emerging noninvasive methylation biomarkers of cancer prognosis and drug response prediction[J]. Seminars in Cancer Biology, 83, 584–595.

    Article  CAS  PubMed  Google Scholar 

  146. Di Noia, V., D’argento, E., Pilotto, S., et al. (2021). Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer overexpressing PD-L1: Results of the exploratory “FoRECATT” study[J]. Cancer Immunology, Immunotherapy, 70(6), 1583–1592.

    Article  PubMed  Google Scholar 

  147. Soda, H., Ogawara, D., Fukuda, Y., et al. (2019). Dynamics of blood neutrophil-related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non-small cell lung cancer: A hypothesis-generating study[J]. Thorac Cancer, 10(2), 341–346.

    Article  CAS  PubMed  Google Scholar 

  148. Prelaj, A., Rebuzzi, S. E., Pizzutilo, P., et al. (2020). EPSILoN: a prognostic score using clinical and blood biomarkers in advanced non–small-cell lung cancer treated with immunotherapy[j]. Clinical Lung Cancer, 21(4), 365–377.e5.

  149. Zhao, Q., Bi, Y., Sun, H., et al. (2021). Serum IL-5 and IFN-gamma are novel predictive biomarkers for anti-PD-1 treatment in NSCLC and GC patients[J]. Disease Markers, 2021, 5526885.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Hellmann, M. D., Janne, P. A., Opyrchal, M., et al. (2021). Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy[J]. Clinical Cancer Research, 27(4), 1019–1028.

    Article  CAS  PubMed  Google Scholar 

  151. Kichenadasse, G., Miners, J. O., Mangoni, A. A., et al. (2020). Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer[J]. JAMA Oncology, 6(4), 512–518.

    Article  PubMed  Google Scholar 

  152. Sridhar, S., Paz-Ares, L., Liu, H., et al. (2019). Prognostic significance of liver metastasis in durvalumab-treated lung cancer patients[J]. Clinical Lung Cancer, 20(6), e601–e608.

    Article  CAS  PubMed  Google Scholar 

  153. Miyawaki, T., Kenmotsu, H., Mori, K., et al. (2020). Association between clinical tumor burden and efficacy of immune checkpoint inhibitor monotherapy for advanced non–small-cell lung cancer[J]. Clinical Lung Cancer, 21(5), e405–e414.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Oxford Science Editing for its editorial support.

Funding

This project was funded by the National Natural Science Foundation of China (81870008 and 81970092).

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  1. Xing Wang, Ziyun Qiao, Beatrice Aramini contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Shanghai General Hospital, Shanghai, China

    Xing Wang, Ziyun Qiao, Dong Lin, Xiaolong Li & Jiang Fan

  2. Division of Thoracic Surgery, Department of Experimental, Diagnostic and Specialty Medicine-DIMES of the Alma Mater Studiorum, G.B. Morgagni–L. Pierantoni Hospital, University of Bologna, Forlì, Italy

    Beatrice Aramini

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Wang, X., Qiao, Z., Aramini, B. et al. Potential biomarkers for immunotherapy in non-small-cell lung cancer. Cancer Metastasis Rev 42, 661–675 (2023). https://doi.org/10.1007/s10555-022-10074-y

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