Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

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

Objectives

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

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AK:

Actinic keratosis

BD:

Bowen´s disease

cSCC:

Cutaneous squamous cell carcinoma

KA:

Keratoacanthoma

NMSC:

Non-melanoma skin cancer

TPS:

Tumour proportion score

UICC:

Union Internationale Contre le Cancer

References

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cockerell CJ (2000) Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol 42:11–17

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 2:89–97

    Article  PubMed  PubMed Central  Google Scholar 

  11. Feldman SR, Fleischer AB Jr (2011) Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis 87:201–207

    PubMed  Google Scholar 

  12. Savage JA, Maize JC Sr (2014) Keratoacanthoma clinical behavior: a systematic review. Am J Dermatopathol 36:422–429. doi:10.1097/DAD.0000000000000031

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 34:4102–4109

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lutz Schmitz.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gambichler, T., Gnielka, M., Rüddel, I. et al. Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma. Cancer Immunol Immunother 66, 1199–1204 (2017). https://doi.org/10.1007/s00262-017-2015-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2015-x

Keywords

Navigation