Document Type : Research articles


1 Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Medical Pathology, Antalya, Turkey

2 Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Otolarngology, Antalya,Turkey


Background: Programmed Death-Ligand 1 (PD-L1) is a cell membrane protein found on the surface of cancer cells, immune system cells in the tumor microenvironment, and various healthy tissues. Moreover, it plays a key role in suppressing the immune system.
Objectives: We aim to explain the presence of PD-L1 in Head-Neck Squamosus Cell Carcinomas (HNSCC) and premalign lesions by immunohistochemical method.
Methods: Our retrospective study included 22 patients with HNSCC (15(68.1%) Oral cavity and 7(31.9%) Oropharynx), 20 patients with oral lichen planus, and 14 patients with normal oral cavity mucosa. In the evaluation of PD-L1 antibodies applied immunohistochemically in patients with HNSCC, the percentage of tumor cells showing membranous staining with PD-L1 antibodies was calculated.
Results: The mean age of HNSCC patients participating in the study was 52.24 ± 11.7 years, the mean age of oral lichen planus patients was 34.10 ± 9.8 years, and the control patients' mean age was 31.42 ± 10.6 years. The rate of PD-L1 staining of tumor cells of HNSCC patients was significantly higher than the control group (P=0.001).
Conclusion: The importance of PD-L1 expression in HNSCC and precancerous lesions of the oral cavity is remarkable, and the values may be related to the pathophysiology of these diseases.


  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90. doi: 10.3322/caac.20107.
  2. Wyss A, Hashibe M, Chuang SC, Lee YC, Zhang ZF, Yu GP, et al. Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the international head and neck cancer epidemiology consortium. Am J Epidemiol. 2013;178(5):679–90. doi: 10.1093/aje/kwt029. [PubMed: 23817919].
  3. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73(6):1733–41. doi: 10.1158/0008-5472.can-12-2384. [PubMed: 23288508].
  4. Liao W, Zheng H, Wu S, Zhang Y, Wang W, Zhang Z, et al. The systemic activation of programmed death 1-PD-L1 axis protects systemic lupus erythematosus model from Nephritis. Am J Nephrol. 2017;46(5):371-9. doi: 10.1159/000480641. [PubMed: 29069649].
  5. Canavan M, Floudas A, Veale DJ, Fearon U. The PD-1:PD-L1 axis in ınflammatory arthritis. BMC Rheumatol. 2021;5(1):1. doi: 10.1186/s41927-020-00171-2. [PubMed: 33423684].
  6. Zhou QH, Li KW, Chen X, He HX, Peng SM, Peng SR, et al. HLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma. J Immunother Cancer. 2020;8(1):e000157. doi: 10.1136/jitc-2019-000157. [PubMed: 31959726].
  7. Ettrich TJ, Seufferlein T. Systemic therapy for metastatic Pancreatic Cancer. Curr Treat Options Oncol. 2021;22(11):106. doi: 10.1007/s11864-021-00895-4. [PubMed: 34665339].
  8. Gil Del Alcazar CR, Trinh A, Alečković M, Rojas Jimenez E, Harper NW, Oliphant MU, et al. Insights into ımmune escape during tumor evolution and response to ımmunotherapy using a rat model of Breast Cancer. Cancer Immunol Res. 2022;10(6):680-97. doi: 10.1158/2326-6066.CIR-21-0804. [PubMed: 35446942].
  9. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. doi: 10.3390/cancers12030738. [PubMed: 32245016].
  10. Gregoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(5):184–6. doi: 10.1093/annonc/mdq185. [PubMed: 20555077].
  11. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, et al. Head and neck cancers, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(7):873-98. doi: 10.6004/jnccn.2020.0031. [PubMed: 32634781].
  12. Saâda-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28(7):1605-11. doi: 10.1093/annonc/mdx178. [PubMed: 28419181].
  13. Meulenaere A, Vermassen T, Aspeslagh S, Huvenne W, Dorpe JV, Ferdinande L, et al. Turning the tide: Clinical utility of PD-L1 expression in squamous cell carcinoma of the head and neck. Oral Oncol. 2017;70:34-42. doi: 10.1016/j.oraloncology.2017.05.002. [PubMed: 28622889].
  14. Martinez Marti A, Martinez P, Navarro A, Cedres S, Murtra-Garrell N, Salva F, et al. Concordance of PD-L1 expression by different immunohistochemistry (IHC) definitions and in situ hybridization (ISH) in squamous cell carcinoma (SCC) of the lung. J Clin Oncol. 2014;15:7569. doi: 10.1200/jco.2014.32.15_suppl.7569.
  15. Ferris RL, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67. doi: 10.1056/NEJMoa1602252. [PubMed: 27718784].
  16. Kim HS, Lee JY, Lim SH, Park K, Sun JM, Ko YH, et al. Association between PD-L1 and HPV status and the prognostic value of PD-L1 in oropharyngeal squamous cell carcinoma. Cancer Res Treat. 2016;48(2):527–36. doi: 10.4143/crt.2015.249. [PubMed: 26511814].
  17. Feldman R, Gatalica Z, Knezetic J, Reddy S, Nathan CA, Javadi N, et al. Molecular profiling of head and neck squamous cell carcinoma. Head Neck. 2016;38(1):1625–38. doi: 10.1002/ hed.24290. [PubMed: 26614708].
  18. Abdel-Rahman O. Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis. Crit Rev Oncol Hematol. 2016;101:75-85. doi: 10.1016/j.critrevonc.2016.03.007. [PubMed: 26969107].
  19. Cho YA, Yoon H Y, Lee J, Hong SP, Hong SD. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncology. 2011;47(12):
  20. -53. doi: 10.1016/j.oraloncology.2011.08.007. [PubMed: 21911310].
  21. Satgunaseelan L, Gupta R, Madore J, Chia N, Lum T, Palme CE, et al. Programmed cell death-ligand 1 expression in
  22. oral squamous cell carcinoma is associated with an inflammatory phenotype. Pathology. 2016;48(6):574–80. doi: 10.1016/j.pathol.2016.07.003. [PubMed: 27590194].
  23. Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K. Tumorinfiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(5):744–52. Doi: 10.1016/j.tripleo.2009.12.015. [PubMed: 20303300].
  24. Qiao B, Huang J, Mei Z, Lam AK, Zhao J, Ying L. Analysis of ımmune microenvironment by multiplex ımmunohistochemistry staining in different oral diseases and oral squamous cell carcinoma.
  25. Front Oncol. 2020;10:555757. doi: 10.3389/fonc.2020.555757. [PubMed: 33364188].
  26. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-74. doi: 10.1158/1078-0432.CCR-13-3271. [PubMed: 24714771].
  27. Oliveira-Costa JP, de Carvalho AF, da Silveira da GG, Amaya P, Wu Y, Park KJ, et al. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget. 2015;6(25):20902-20. doi: 10.18632/oncotarget.3939. [PubMed: 26041877].
  28. Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol. 2013;31(33):4252-9. doi: 10.1200/JCO.2013.51.3002. [PubMed: 24127443].
  29. Chen XJ, Tan YQ, Zhang N, He MJ, Zhou G. Expression of programmed cell death-ligand 1 in oral squamous cell carcinoma and oral leukoplakia is associated with disease progress and CD8+ tumor-infiltrating lymphocytes. Pathol Res Pract. 2019;215(6):152418. doi: 10.1016/j.prp.2019.04.010. [PubMed: 31027907].
  30. Saraggi D, Galuppini F, Remo A, Urso ED, Bacchin D, Salmaso R, et al. PD‐L1 overexpression in ampulla of Vater carcinoma and its pre‐invasive lesions. Histopathology. 2017;71(3):470-4. doi: 10.1111/his.13254. [PubMed: 28502094].
  31. Belkhir R, Burel S, Dunogeant L, Marabelle A, Hollebecque A, Besse B, et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis. 2017;76(10):1747-50. Doi: 10.1136/annrheumdis-2017-211216. [PubMed: 28600350].
  32. Bertsias GK, Nakou M, Choulaki C, Raptopoulou A, Papadimitraki A, Goulielmos G, et al. Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus. Arthritis Rheum. 2009;60(1):207-18. doi: 10.1002/art.24227. [PubMed: 19116915].
  33. Ghanizada M, Jakobsen KK, Gronhoj C, Buchwald VC. The effects of checkpoint inhibition on head and neck squamous cell carcinoma: A systematic review. Oral Oncol. 2019;90:67-73. doi: 10.1016/j.oraloncology.2019.01.018. [PubMed: 30846179].