Cancer Immunology, Immunotherapy

, Volume 66, Issue 9, pp 1199–1204 | Cite as

Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma

  • Thilo Gambichler
  • Martha Gnielka
  • Ines Rüddel
  • Eggert Stockfleth
  • Markus Stücker
  • Lutz SchmitzEmail author
Original Article



Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers.


To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA).


We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed.


PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001). A similar correlation was also found for cSCC (r = 0.86; P < 0.0001). The percentage of PD-L1 + tumours was 33.3% for KA and 26.9% for cSCC. Similarly, the percentage of PD-L1 + TILs in KA and cSCC was 33.3 and 34.6%, respectively.


PD-L1 is differently expressed in cSCC and closely related non-melanoma skin cancer. cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD1/PD-L1 inhibitors might be beneficial in a proportion of patients with an inoperable or metastatic cSCC. Unlike AK and BD, TILs and tumour cells of KA and cSCC present very similar PD-L1 expression profiles indicating a common immune escape mechanism.


PD-L1 Keratoacanthoma Actinic keratosis Bowen’s disease Squamous cell carcinoma Tumour-infiltrating lymphocyte 



Actinic keratosis


Bowen´s disease


Cutaneous squamous cell carcinoma




Non-melanoma skin cancer


Tumour proportion score


Union Internationale Contre le Cancer



This work is part of the doctoral thesis of Martha Gnielka.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Stratigos A, Garbe C, Lebbe C et al (2015) Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer 51:1989–2007. doi: 10.1016/j.ejca.2015.06.110 CrossRefPubMedGoogle Scholar
  2. 2.
    Burton KA, Ashack KA, Khachemoune A (2016) Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol 17:491–508. doi: 10.1007/s40257-016-0207-3 CrossRefPubMedGoogle Scholar
  3. 3.
    Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17:e542–e551. doi: 10.1016/S1470-2045(16)30406-5 CrossRefPubMedGoogle Scholar
  4. 4.
    Belai EB, de Oliveira CE, Gasparoto TH, Ramos RN, Torres SA, Garlet GP, Cavassani KA, Silva JS, Campanelli AP (2014) PD-1 blockage delays murine squamous cell carcinoma development. Carcinogenesis 35:424–431. doi: 10.1093/carcin/bgt305 CrossRefPubMedGoogle Scholar
  5. 5.
    Kallini JR, Hamed N, Khachemoune A (2015) Squamous cell carcinoma of the skin: epidemiology, classification, management, and novel trends. Int J Dermatol 54:130–140. doi: 10.1111/ijd.12553 CrossRefPubMedGoogle Scholar
  6. 6.
    Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, Zhang G (2016) A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway and translational blockade of immune checkpoints. Int J Mol Sci. doi: 10.3390/ijms17071151 Google Scholar
  7. 7.
    Lyford-Pike S, Peng S, Young GD et al (2013) 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 73:1733–1741. doi: 10.1158/0008-5472.CAN-12-2384 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cockerell CJ (2000) Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol 42:11–17CrossRefPubMedGoogle Scholar
  9. 9.
    Batinac T, Zamolo G, Coklo M, Hadzisejdic I (2006) Possible key role of granzyme B in keratoacanthoma regression. Med Hypotheses 66:1129–1132. doi: 10.1016/j.mehy.2005.12.035 CrossRefPubMedGoogle Scholar
  10. 10.
    Bayer-Garner IB, Ivan D, Schwartz MR, Tschen JA (2004) The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res. 2:89–97CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Feldman SR, Fleischer AB Jr (2011) Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis 87:201–207PubMedGoogle Scholar
  12. 12.
    Savage JA, Maize JC Sr (2014) Keratoacanthoma clinical behavior: a systematic review. Am J Dermatopathol 36:422–429. doi: 10.1097/DAD.0000000000000031 CrossRefPubMedGoogle Scholar
  13. 13.
    Slater NA, Googe PB (2016) PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J Cutan Pathol 43:663–670. doi: 10.1111/cup.12728 CrossRefPubMedGoogle Scholar
  14. 14.
    Jiao Q, Liu C, Li W, Li W, Fang F, Qian Q, Zhang X (2017) Programmed death-1 ligands 1 and 2 expression in cutaneous squamous cell carcinoma and their relationship with tumour-infiltrating dendritic cells. Clin Exp Immunol. doi: 10.1111/cei.12921 PubMedGoogle Scholar
  15. 15.
    Aguiar PN Jr, Santoro IL, Tadokoro H, de Lima Lopes G, Filardi BA, Oliveira P, Castelo-Branco P, Mountzios G, de Mello RA (2016) A pooled analysis of nivolumab for the treatment of advanced non-small-cell lung cancer and the role of PD-L1 as a predictive biomarker. Immunotherapy. 8:1011–1019. doi: 10.2217/imt-2016-0032 CrossRefPubMedGoogle Scholar
  16. 16.
    Ascierto ML, McMiller TL, Berger AE et al (2016) The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma. Cancer Immunol Res 4:726–733. doi: 10.1158/2326-6066.CIR-16-0072 CrossRefPubMedGoogle Scholar
  17. 17.
    Daud AI, Wolchok JD, Robert C et al (2016) Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34:4102–4109CrossRefPubMedGoogle Scholar
  18. 18.
    Borradori L, Sutton B, Shayesteh P, Daniels GA (2016) Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol 175:1382–1386. doi: 10.1111/bjd.14642 CrossRefPubMedGoogle Scholar
  19. 19.
    Chang AL, Kim J, Luciano R, Sullivan-Chang L, Colevas AD (2016) A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. JAMA Dermatol. 152:106–108. doi: 10.1001/jamadermatol.2015.2705 CrossRefPubMedGoogle Scholar
  20. 20.
    Winkler JK, Schneiderbauer R, Bender C, Sedlaczek O, Frohling S, Penzel R, Enk A, Hassel JC (2017) Anti-programmed cell death-1 therapy in nonmelanoma skin cancer. Br J Dermatol 176:498–502. doi: 10.1111/bjd.14664 CrossRefPubMedGoogle Scholar
  21. 21.
    Schaper K, Kother B, Hesse K, Satzger I, Gutzmer R (2016) The pattern and clinicopathological correlates of programmed death-ligand 1 expression in cutaneous squamous cell carcinoma. Br J Dermatol. doi: 10.1111/bjd.14955 Google Scholar
  22. 22.
    Kim HR, Ha SJ, Hong MH et al (2016) PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep. 6:36956. doi: 10.1038/srep36956 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M (2004) B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 10:5094–5100. doi: 10.1158/1078-0432.CCR-04-0428 CrossRefPubMedGoogle Scholar
  24. 24.
    Lipson EJ, Vincent JG, Loyo M et al (2013) PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 1:54–63. doi: 10.1158/2326-6066.CIR-13-0034 CrossRefPubMedGoogle Scholar
  25. 25.
    Mu CY, Huang JA, Chen Y, Chen C, Zhang XG (2011) High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 28:682–688. doi: 10.1007/s12032-010-9515-2 CrossRefPubMedGoogle Scholar
  26. 26.
    Song M, Chen D, Lu B et al (2013) PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS ONE 8:e65821. doi: 10.1371/journal.pone.0065821 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Taube JM, Anders RA, Young GD et al (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4:127ra37. doi: 10.1126/scitranslmed.3003689 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vassilakopoulou M, Avgeris M, Velcheti V et al (2016) Evaluation of PD-L1 expression and associated tumor-infiltrating lymphocytes in laryngeal squamous cell carcinoma. Clin Cancer Res 22:704–713. doi: 10.1158/1078-0432.CCR-15-1543 CrossRefPubMedGoogle Scholar
  29. 29.
    Wang X, Teng F, Kong L, Yu J (2016) PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 9:5023–5039. doi: 10.2147/OTT.S105862 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Thilo Gambichler
    • 1
  • Martha Gnielka
    • 1
  • Ines Rüddel
    • 1
  • Eggert Stockfleth
    • 1
  • Markus Stücker
    • 1
  • Lutz Schmitz
    • 1
    Email author
  1. 1.Skin Cancer Center of the Department of Dermatology, St. Josef HospitalRuhr-University BochumBochumGermany

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