#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Programmed Death-Ligand 1 Expression in Non-Small Cell Lung Carcinoma Biopsies and Its Association with Tumor Infi ltrat ing Lymphocytes and the Degree of Desmoplasia


Authors: V. Tancoš 1;  M. Grendár 2;  A. Farkašová 3;  Z. Huťka 1;  Z. Kviatkovská 1;  L. Plank 1,3
Authors‘ workplace: Ústav patologickej anatómie JLF UK a UN Martin, Slovenská republika 1;  Ústav bio informatiky, Martinské centrum pre bio medicínu, JLF v Martine, UK v Bratislave, Slovenská republika 2;  Martinské bio ptické centrum, s. r. o., Martin, Slovenská republika 3
Published in: Klin Onkol 2020; 33(1): 55-65
Category: Original Articles
doi: https://doi.org/10.14735/amko202055

Overview

Background: Immunotherapy blocking the PD-1/PD-L1 signalling pathway has become a dominant treatment modality for patients with non-small cell lung carcinoma (NSCLC). Programmed death-ligand 1 (PD-L1) expression on the membrane of tumour cells and/or tumour infiltrating lymphocytes (TIL) evaluated immunohistochemically is still the only clinically validated predictive biomarker for immunotherapy, but it has its limitations. TIL in the tumour microenviroment was identified as having predictive value. We retrospectively evaluated 134 NSCLC resection specimens, and analysed the association between PD-L1 expression, the presence of TIL, and the degree of desmoplasia in tumours.

Material and methods: PD-L1 expression on tumour cells and TIL were evaluated immunohistochemically using the anti-PD-L1 antibody (clone 22C3) and the anti-CD3 antibody (polyclone), respectively. PD-L1 was scored using the “tumour proportion score” (TPS) system with three categories: TPS < 1%, 1–49%, and ≥ 50%. TIL were evaluated semiquantitatively using the “percentage of stromal TIL” (PST) system, and categories of PST < 10%, 10–49% and ≥ 50% were recorded. The association between PD-L1 expression in tumour cells and TIL was compared with the PST value. Statistical analysis was conducted using the Cochran-Armitage test, and a p-value < 5% was considered significant.

Results: PD-L1 expression was significantly higher in PST 10–49% and ≥ 50% categories than in the PST < 10% category in grade 1 and grade 2 adenocarcinomas (p = 0.008), grade 3 adenocarcinomas (p = 0.009), and squamous cell carcinomas (p = 0.028). PD-L1 expression in TIL was associated with the PST value in squamous cell carcinomas (p = 0.025) but not in adenocarcinomas. Desmoplastic tumours had particularly low TPS and PST values.

Conclusion: PD-L1 expression in NSCLC is associated with the presence of TIL. Desmoplastic areas in tumours represent immunologically inactive tumour microenviroments. Administration of anti-PD-1/PD-L1 immunotherapy, together with agents blocking the TGF-β signalling pathway, represent a promising combinational therapy for patients with desmoplastic NSCLC.

The authors declare they have no potential confl cts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 25. 11. 2019

Accepted: 8. 12. 2019

Keywords:

programmed death-ligand 1 – non-small cell lung carcinoma – tumour infiltrating lymphocytes – predictive biomarker


Sources

1. Travis WD, Brambilla E, Burke AP et al (eds). WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon: IARC 2015.

2. Bílek O, Bohovicová L, Demlová R et al. Non-small cell lung cancer – from immunobiology to immunotherapy. Klin Onkol 2016; 29 (Suppl 4): 78–87. doi: 10.14735/amko20164S78.

3. Zatloukalová, Pjechová M, Babčanová S et al. The role of PD-1/PD-L1 signaling pathway in antitumor immune response. Klin Onkol 2016; 29 (Suppl 4): 72–77. doi: 10.14735/amko20164S72.

4. Schvartsman G, Ferrarotto R, Massarelli E. Checkpoint inhibitors in lung cancer: latest developments and clinical potential. Ther Adv Med Oncol 2016; 8 (6): 460–473. doi: 10.1177/1758834016661164.

5. Fiala O, Šorejs O, Pešek M et al. Immunotherapy in the treatment of lung cancer. Klin Onkol 2017; 30 (Suppl 3): 22–31. doi: 10.14735/amko20173S22.

6. Yan YF, Zheng YF, Ming PP et al. Immune checkpoint inhibitors in non-small-cell lung cancer: current status and future directions. Brief Funct Genomics 2018; 18 (2): 147–156. doi: 10.1093/bfgp/ely029.

7. Mathew M, Safyan RA, Shu CA. PD-L1 as a biomarker in NSCLC: challenges and future directions. Ann Transl Med 2017; 5 (18): 375. doi: 10.21037/atm.2017.08.04.

8. Gridelli C, Ardizzoni A, Barberis M et al. Predictive biomarkers of immunotherapy for non-small cell lung cancer: results from an Experts Panel Meeting of the Italian Association of Thoracic Oncology. Transl Lung Cancer Res 2017; 6 (3): 373–386. doi: 10.21037/tlcr.2017.05.09.

9. Schalper KA, Brown J, Carvajal-Hausdorf D et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 2015; 107 (3): pii: dju435. doi: 10.1093/jnci/dju435.

10. Tokito T, Azuma K, Kawahara A et al. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 2016; 55 (1): 7–14. doi: 10.1016/j.ejca.2015.11.020.

11. Solomon B, Young RJ, Bressel M et al. Prognostic significance of PD-L1+ and CD8+ immune cells in HPV+ oropharyngeal squamous cell carcinoma. Cancer Immunol Res 2018; 6 (3): 295–304. doi: 10.1158/2326-6066.

12. 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. doi: 10.1016/j.jtho.2016.11.2228.

13. Salgado R, Denkert C, Demaria S et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015; 26 (2): 259–271. doi: 10.1093/annonc/mdu450.

14. Teng MW, Ngiow SF, Ribas A et al. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015; 75 (11): 2139–2145. doi: 10.1158/0008-5472.CAN-15-0255.

15. Lin G, Fan X, Zhu W et al. Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget 2017; 8 (48): 83986–83994. doi: 10.18632/oncotarget.20233.

16. He Y, Rozeboom L, Rivard CJ et al. PD-1, PD-L1 protein expression in non-small cell lung cancer and their relationship with tumor-infiltrating lymphocytes. Med Sci Monit 2017; 23 (1): 1208–1216. doi: 10.12659/MSM.899909.

17. Velcheti V, Schalper KA, Carvajal DE et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014; 94 (1): 107–116. doi: 10.1038/ labinvest.2013.130.

18. Kim S, Kim MY, Koh J et al. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer 2015; 51 (17): 2698–2707. doi: 10.1016/j.ejca.2015.08.013.

19. Mori S, Motoi N, Ninomiya H et al. High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth-factor receptor cases. Pathol Int 2017; 67 (1): 37–44. doi: 10.1111/pin.12489.

20. Koh J, Go H, Keam B et al. Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status. Mod Pathol 2015; 28 (9): 1154–1166. doi: 10.1038/modpathol.2015.63.

21. Cha YJ, Kim HR, Lee CY et al. Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status. Lung Cancer 2016; 97 (1): 73–80. doi: 10.1016/j.lungcan.2016.05.001.

22. Shimoji M, Shimizu S, Sato K et al. Clinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1). Lung Cancer 2016; 98 (1): 69–75. doi: 10.1016/j.lungcan.2016.04.021.

23. Takada K, Okamoto T, Shoji F et al. Clinical significance of PD-L1 protein expression in surgically resected primary lung adenocarcinoma. J Thorac Oncol 2016; 11 (11): 1879–1890. doi: 10.1016/j.jtho.2016.06.006.

24. Mariathasan S, Turley SJ, Nickles D et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554 (7693): 544–548. doi: 10.1038/nature25501.

25. Ravi R, Noonan KA, Pham V et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018; 9 (1): 741. doi: 10.1038/s41467-017-02696-6.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#