Clinical utility of PD-L1 expression in circulating tumor cells in non-small cell lung cancer patients treated with immunotherapy_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Yadong ¹ , YANG Xiaoying ^1,2 , JIA Ziqi ^1,2 , BING Zhongxing ¹ , YANG Huaxia ³ , YANG Yanlian ⁴ , HU Zhiyuan ⁴ , LI Shanqing ¹ ,  LIANG Naixin ¹

1. Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, P.R.China;
2. Peking Union Medical College, Eight-Year MD Program, Beijing, 100005, P.R.China;
3. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, P.R.China;
4. National Center for Nannoscience and Technology, Beijing, 100190, P.R.China;

Corresponding author：

LIANG Naixin, Email: pumchnelson@163.com

Keywords：

Circulating tumor cells; programmed cell death-ligand 1(PD-L1); non-small cell lung cancer; immunotherapy; review

DOI：

10.7507/1007-4848.202003026

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Lung cancer is the most frequent cancer and the leading cause of cancer death all around the world. Anti-programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) therapies have significantly improved the outcomes of non-small cell lung cancer (NSCLC) patients in recent years. However, the objective response rate in non-screened patients is only about 20%. It is very important to screen out the potential patients suitable for immunotherapy. Immunohistochemical staining of tumor tissue biopsies with PD-L1 antibodies can predict the therapeutic response to immunotherapy to some extent, but it still has some limitations. Recently some clinical studies have shown that PD-L1 expression in circulating tumor cells (CTC-PD-L1) is a potential independent biomarker and may provide important information for immunotherapy in NSCLC. This article will review technology for CTC-PD-L1 detection and the predictive value of CTC-PD-L1 for immunotherapy in NSCLC and review the latest clinical research progress.

Citation： WANG Yadong, YANG Xiaoying, JIA Ziqi, BING Zhongxing, YANG Huaxia, YANG Yanlian, HU Zhiyuan, LI Shanqing, LIANG Naixin. Clinical utility of PD-L1 expression in circulating tumor cells in non-small cell lung cancer patients treated with immunotherapy. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(1): 110-115. doi: 10.7507/1007-4848.202003026 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
3.	Reck M, Rabe KF. Precision diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med, 2017, 377(9): 849-861.
4.	Antonia SJ, Borghaei H, Ramalingam SS, et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol, 2019, 20(10): 1395-1408.
5.	Herbst RS, Garon EB, Kim DW, et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the keynote-010 study. J Clin Oncol, 2020, JCO1902446.
6.	Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med, 2018, 378(24): 2288-2301.
7.	Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
8.	Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015, 348(6230): 124-128.
9.	Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med, 2015, 373(2): 123-135.
10.	Ilie M, Long-Mira E, Bence C, 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, 2016, 27(1): 147-153.
11.	Büttner R, Gosney JR, Skov BG, et al. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol, 2017, 35(34): 3867-3876.
12.	Vilain RE, Menzies AM, Wilmott JS, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res, 2017, 23(17): 5024-5033.
13.	Lantuejoul S, Sound-Tsao M, Cooper WA, et al. PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee. J Thorac Oncol, 2020, 15(4): 499-519.
14.	Follain G, Herrmann D, Harlepp S, et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer, 2020, 20(2): 107-124.
15.	Chemi F, Rothwell DG, Mcgranahan N, et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat Med, 2019, 25(10): 1534-1539.
16.	Ashworth TR. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Australas Med J, 1869, 14: 146-147.
17.	Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol, 2019, 16(7): 409-424.
18.	Mazel M, Jacot W, Pantel K, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol, 2015, 9(9): 1773-1782.
19.	Nicolazzo C, Raimondi C, Mancini M, et al. Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor nivolumab. Sci Rep, 2016, 6(1): 31726.
20.	Guibert N, Delaunay M, Lusque A, et al. PD-L1 expression in circulating tumor cells of advanced non-small cell lung cancer patients treated with nivolumab. Lung Cancer, 2018, 120: 108-112.
21.	Kulasinghe A, Kapeleris J, Kimberley R, et al. The prognostic significance of circulating tumor cells in head and neck and non-small-cell lung cancer. Cancer Med, 2018, 7(12): 5910-5919.
22.	Dhar M, Wong J, Che J, et al. Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer. Sci Rep, 2018, 8(1): 2592.
23.	Bao H, Bai T, Takata K, et al. High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab. Oncol Lett, 2018, 15(3): 3061-3067.
24.	Janning M, Kobus F, Babayan A, 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, 2019, 11(6): 835.
25.	Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non–small-cell lung cancer. J Clin Oncol, 2011, 29(12): 1556-1563.
26.	Frick MA, Feigenberg SJ, Jean-Baptiste SR, et al. Circulating tumor cells are associated with recurrent disease in patients with early stage non-small cell lung cancer treated with stereotactic body radiation therapy. Clin Cancer Res, 2020.
27.	Tamminga M, de Wit S, Schuuring E, et al. Circulating tumor cells in lung cancer are prognostic and predictive for worse tumor response in both targeted- and chemotherapy. Transl Lung Cancer Res, 2019, 8(6): 854-861.
28.	Castello A, Carbone FG, Rossi S, et al. Circulating tumor cells and metabolic parameters in NSCLC patients treated with checkpoint inhibitors. Cancers, 2020, 12(2): 487.
29.	Tamminga M, de Wit S, Hiltermann TJN, et al. Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors. J Immunother Cancer, 2019, 7(1): 173.
30.	Alama A, Coco S, Genova C, et al. Prognostic relevance of circulating tumor cells and circulating cell-free DNA association in metastatic non-small cell lung cancer treated with nivolumab. J Clin Med, 2019, 8(7): 1011.
31.	Adams DL, Adams DK, He J, et al. Sequential tracking of PD-L1 expression and RAD50 induction in circulating tumor and stromal cells of lung cancer patients undergoing radiotherapy. Clin Cancer Res, 2017, 23(19): 5948-5958.
32.	Wang Y, Kim TH, Fouladdel S, et al. PD-L1 expression in circulating tumor cells increases during radio(chemo)therapy and indicates poor prognosis in non-small cell lung cancer. Sci Rep, 2019, 9(1): 566.
33.	Kotsakis A, Kallergi G, Aggouraki D, et al. CD8(+) PD-1(+) T-cells and PD-L1(+) circulating tumor cells in chemotherapy-naive non-small cell lung cancer: towards their clinical relevance? Ther Adv Med Oncol, 2019, 11: 1758835919853193.
34.	Kallergi G, Vetsika EK, Aggouraki D, et al. Evaluation of PD-L1/PD-1 on circulating tumor cells in patients with advanced non-small cell lung cancer. Ther Adv Med Oncol, 2018, 10: 1758834017750121.
35.	Ilie M, Szafer-Glusman E, Hofman V, 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, 2018, 29(1): 193-199.
36.	Dong J, Zhu D, Tang X, et al. Circulating tumor cells in pulmonary vein and peripheral arterial provide a metric for PD-L1 diagnosis and prognosis of patients with non-small cell lung cancer. PLoS One, 2019, 14(7): e0220306.
37.	Dong J, Zhu D, Tang X, et al. Detection of circulating tumor cell molecular subtype in pulmonary vein predicting prognosis of stage Ⅰ-Ⅲ non-small cell lung cancer patients. Front Oncol, 2019, 9: 1139.
38.	Boffa DJ, Graf RP, Salazar MC, et al. Cellular expression of PD-L1 in the peripheral blood of lung cancer patients is associated with worse survival. Cancer Epidemiol Biomarkers Prev, 2017, 26(7): 1139-1145.
39.	Raimondi C, Carpino G, Nicolazzo C, et al. PD-L1 and epithelial-mesenchymal transition in circulating tumor cells from non-small cell lung cancer patients: A molecular shield to evade immune system? Oncoimmunology, 2017, 6(12): e1315488.
40.	Manjunath Y, Upparahalli SV, Avella DM, et al. PD-L1 expression with epithelial mesenchymal transition of circulating tumor cells is associated with poor survival in curatively resected non-small cell lung cancer. Cancers, 2019, 11(6): 806.
41.	Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol, 2018, 4(11): 1543-1552.
42.	Scharpenseel H, Hanssen A, Loges S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep, 2019, 9(1): 7406.
43.	Hirsch FR, Mcelhinny A, Stanforth D, 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, 2017, 12(2): 208-222.
44.	Tsao MS, Kerr KM, Kockx M, et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol, 2018, 13(9): 1302-1311.
45.	Strati A, Koutsodontis G, Papaxoinis G, et al. Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma. Ann Oncol, 2017, 28(8): 1923-1933.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
3. Reck M, Rabe KF. Precision diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med, 2017, 377(9): 849-861.
4. Antonia SJ, Borghaei H, Ramalingam SS, et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol, 2019, 20(10): 1395-1408.
5. Herbst RS, Garon EB, Kim DW, et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the keynote-010 study. J Clin Oncol, 2020, JCO1902446.
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med, 2018, 378(24): 2288-2301.
7. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC. N Engl J Med, 2018, 379(24): 2342-2350.
8. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015, 348(6230): 124-128.
9. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med, 2015, 373(2): 123-135.
10. Ilie M, Long-Mira E, Bence C, 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, 2016, 27(1): 147-153.
11. Büttner R, Gosney JR, Skov BG, et al. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol, 2017, 35(34): 3867-3876.
12. Vilain RE, Menzies AM, Wilmott JS, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res, 2017, 23(17): 5024-5033.
13. Lantuejoul S, Sound-Tsao M, Cooper WA, et al. PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee. J Thorac Oncol, 2020, 15(4): 499-519.
14. Follain G, Herrmann D, Harlepp S, et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer, 2020, 20(2): 107-124.
15. Chemi F, Rothwell DG, Mcgranahan N, et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat Med, 2019, 25(10): 1534-1539.
16. Ashworth TR. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Australas Med J, 1869, 14: 146-147.
17. Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol, 2019, 16(7): 409-424.
18. Mazel M, Jacot W, Pantel K, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol, 2015, 9(9): 1773-1782.
19. Nicolazzo C, Raimondi C, Mancini M, et al. Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor nivolumab. Sci Rep, 2016, 6(1): 31726.
20. Guibert N, Delaunay M, Lusque A, et al. PD-L1 expression in circulating tumor cells of advanced non-small cell lung cancer patients treated with nivolumab. Lung Cancer, 2018, 120: 108-112.
21. Kulasinghe A, Kapeleris J, Kimberley R, et al. The prognostic significance of circulating tumor cells in head and neck and non-small-cell lung cancer. Cancer Med, 2018, 7(12): 5910-5919.
22. Dhar M, Wong J, Che J, et al. Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer. Sci Rep, 2018, 8(1): 2592.
23. Bao H, Bai T, Takata K, et al. High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab. Oncol Lett, 2018, 15(3): 3061-3067.
24. Janning M, Kobus F, Babayan A, 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, 2019, 11(6): 835.
25. Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non–small-cell lung cancer. J Clin Oncol, 2011, 29(12): 1556-1563.
26. Frick MA, Feigenberg SJ, Jean-Baptiste SR, et al. Circulating tumor cells are associated with recurrent disease in patients with early stage non-small cell lung cancer treated with stereotactic body radiation therapy. Clin Cancer Res, 2020.
27. Tamminga M, de Wit S, Schuuring E, et al. Circulating tumor cells in lung cancer are prognostic and predictive for worse tumor response in both targeted- and chemotherapy. Transl Lung Cancer Res, 2019, 8(6): 854-861.
28. Castello A, Carbone FG, Rossi S, et al. Circulating tumor cells and metabolic parameters in NSCLC patients treated with checkpoint inhibitors. Cancers, 2020, 12(2): 487.
29. Tamminga M, de Wit S, Hiltermann TJN, et al. Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors. J Immunother Cancer, 2019, 7(1): 173.
30. Alama A, Coco S, Genova C, et al. Prognostic relevance of circulating tumor cells and circulating cell-free DNA association in metastatic non-small cell lung cancer treated with nivolumab. J Clin Med, 2019, 8(7): 1011.
31. Adams DL, Adams DK, He J, et al. Sequential tracking of PD-L1 expression and RAD50 induction in circulating tumor and stromal cells of lung cancer patients undergoing radiotherapy. Clin Cancer Res, 2017, 23(19): 5948-5958.
32. Wang Y, Kim TH, Fouladdel S, et al. PD-L1 expression in circulating tumor cells increases during radio(chemo)therapy and indicates poor prognosis in non-small cell lung cancer. Sci Rep, 2019, 9(1): 566.
33. Kotsakis A, Kallergi G, Aggouraki D, et al. CD8(+) PD-1(+) T-cells and PD-L1(+) circulating tumor cells in chemotherapy-naive non-small cell lung cancer: towards their clinical relevance? Ther Adv Med Oncol, 2019, 11: 1758835919853193.
34. Kallergi G, Vetsika EK, Aggouraki D, et al. Evaluation of PD-L1/PD-1 on circulating tumor cells in patients with advanced non-small cell lung cancer. Ther Adv Med Oncol, 2018, 10: 1758834017750121.
35. Ilie M, Szafer-Glusman E, Hofman V, 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, 2018, 29(1): 193-199.
36. Dong J, Zhu D, Tang X, et al. Circulating tumor cells in pulmonary vein and peripheral arterial provide a metric for PD-L1 diagnosis and prognosis of patients with non-small cell lung cancer. PLoS One, 2019, 14(7): e0220306.
37. Dong J, Zhu D, Tang X, et al. Detection of circulating tumor cell molecular subtype in pulmonary vein predicting prognosis of stage Ⅰ-Ⅲ non-small cell lung cancer patients. Front Oncol, 2019, 9: 1139.
38. Boffa DJ, Graf RP, Salazar MC, et al. Cellular expression of PD-L1 in the peripheral blood of lung cancer patients is associated with worse survival. Cancer Epidemiol Biomarkers Prev, 2017, 26(7): 1139-1145.
39. Raimondi C, Carpino G, Nicolazzo C, et al. PD-L1 and epithelial-mesenchymal transition in circulating tumor cells from non-small cell lung cancer patients: A molecular shield to evade immune system? Oncoimmunology, 2017, 6(12): e1315488.
40. Manjunath Y, Upparahalli SV, Avella DM, et al. PD-L1 expression with epithelial mesenchymal transition of circulating tumor cells is associated with poor survival in curatively resected non-small cell lung cancer. Cancers, 2019, 11(6): 806.
41. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol, 2018, 4(11): 1543-1552.
42. Scharpenseel H, Hanssen A, Loges S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep, 2019, 9(1): 7406.
43. Hirsch FR, Mcelhinny A, Stanforth D, 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, 2017, 12(2): 208-222.
44. Tsao MS, Kerr KM, Kockx M, et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol, 2018, 13(9): 1302-1311.
45. Strati A, Koutsodontis G, Papaxoinis G, et al. Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma. Ann Oncol, 2017, 28(8): 1923-1933.

Previous Article
Interpretation of the World Cancer Report 2020
Next Article
1 例食管腹段支气管源性食管囊肿行腹腔镜手术切除的诊治体会并文献复习

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Clinical utility of PD-L1 expression in circulating tumor cells in non-small cell lung cancer patients treated with immunotherapy

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content