Skip to main content

Advertisement

SpringerLink
Log in

Differential expression of programmed cell death ligand 1 (PD-L1) and inflammatory cells in basal cell carcinoma subtypes

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Few studies have evaluated programmed cell death ligand (PD-L1) expression and lymphocytic infiltrates in Basal Cell Carcinoma (BCC). The objectives of this study are to assess PD-L1 expression and markers of local immune response in nodular, superficial, and morpheaform BCC, and compare it to normal, sun-exposed skin from the periphery of intradermal nevi. This was a retrospective study that included three histological subtypes of BCCs, and sun-exposed skin from the periphery of dermal nevi as quality controls. Tissue microarrays (TMA) were constructed with subsequent staining of H&E and immunohistochemistry (IHC) for CD4, CD8, FOXP3 and PD-L1. Non-automated quantification of the infiltrate in the intratumoral and stromal compartments on TMAs was performed. A total of 115 BCC (39 nodular, 39 morpheaform, and 37 superficial) and 41 sun-exposed skin samples were included (mean age 65.4 years; 52.6% females). BCC showed higher expression of PD-L1 (5.4 vs 0.7%, p < 0.001), CD8 (29.8 vs 19.7%, p = 0.002), and FOXP3 (0.3 vs 0.06%, p = 0.022) compared to sun-exposed skin. There was a higher PD-L1 expression in nodular BCC compared with other subtypes. Low-risk BCC subtypes (superficial and nodular) exhibited more PD-L1 expression in intratumoral and stromal immune infiltrates as compared to high-risk BCC subtypes. As a limitation, no immune cells function was evaluated in this study, only the presence/absence of T-lymphocyte sub-populations was recorded. Substantial differences in both PD-L1 expression and lymphocytic infiltrates were found amongst the histological subtypes of BCC and sun-exposed skin. Highest PD-L1 expression was found in nodular BCCs which suggests a potentially targetable strategy in the treatment of this most common BCC subtype.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cameron MC, Lee E, Hibler BP, Barker CA, Mori S, Cordova M et al (2019) Basal cell carcinoma: epidemiology; pathophysiology; clinical and histological subtypes; and disease associations. J Am Acad Dermatol 80(2):303–317

    Article  PubMed  Google Scholar 

  2. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM (2015) Incidence estimate of nonmelanoma skin cancer (Keratinocyte Carcinomas) in the U.S. population, 2012. JAMA Dermatol 151(10):1081–1086

    Article  PubMed  Google Scholar 

  3. Staples M, Marks R, Giles G (1998) Trends in the incidence of non-melanocytic skin cancer (NMSC) treated in Australia 1985–1995: are primary prevention programs starting to have an effect? Int J Cancer 78(2):144–148

    Article  CAS  PubMed  Google Scholar 

  4. Goldenberg G, Karagiannis T, Palmer JB, Lotya J, O’Neill C, Kisa R et al (2016) Incidence and prevalence of basal cell carcinoma (BCC) and locally advanced BCC (LABCC) in a large commercially insured population in the United States: a retrospective cohort study. J Am Acad Dermatol 75(5):957-966.e2

    Article  PubMed  Google Scholar 

  5. Guy GP, Machlin SR, Ekwueme DU, Yabroff KR (2015) Prevalence and costs of skin cancer treatment in the U.S., 2002–2006 and 2007–2011. Am J Prev Med 48(2):183–187

    Article  PubMed  Google Scholar 

  6. Ozgediz D, Smith EB, Zheng J, Otero J, Tabatabai ZL, Corvera CU (2008) Basal cell carcinoma does metastasize. Dermatol Online J 14(8):5

    Article  PubMed  Google Scholar 

  7. Mohan SV, Chang ALS (2014) Advanced basal cell carcinoma: epidemiology and therapeutic innovations. Curr Dermatol Rep 3(1):40–45

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rudin CM (2012) Vismodegib. Clin Cancer Res 18(12):3218–3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wahid M, Jawed A, Mandal RK, Dar SA, Khan S, Akhter N et al (2016) Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas. Crit Rev Oncol Hematol 98:235–241

    Article  PubMed  Google Scholar 

  10. Odom D, Mladsi D, Purser M, Kaye JA, Palaka E, Charter A et al (2017) A matching-adjusted indirect comparison of sonidegib and vismodegib in advanced basal cell carcinoma. J Skin Cancer 2017:6121760

    Article  PubMed  PubMed Central  Google Scholar 

  11. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J-J, Rutkowski P, Lao CD et al (2019) Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381(16):1535–1546

    Article  CAS  PubMed  Google Scholar 

  12. Robert C, Ribas A, Schachter J, Arance A, Grob J-J, Mortier L et al (2019) Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 20(9):1239–1251

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Migden MR, Khushalani NI, Chang ALS, Lewis KD, Schmults CD, Hernandez-Aya L et al (2020) Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 21(2):294–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lipson EJ, Lilo MT, Ogurtsova A, Esandrio J, Xu H, Brothers P et al (2017) Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer 5:23

    Article  PubMed  PubMed Central  Google Scholar 

  16. Falchook GS, Leidner R, Stankevich E, Piening B, Bifulco C, Lowy I et al (2016) Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer 4:70

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ikeda S, Goodman AM, Cohen PR, Jensen TJ, Ellison CK, Frampton G et al (2016) Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. NPJ Genomic Med. https://doi.org/10.1038/npjgenmed.2016.37

    Article  Google Scholar 

  18. Winkler JK, Schneiderbauer R, Bender C, Sedlaczek O, Fröhling S, Penzel R et al (2017) Anti-programmed cell death-1 therapy in nonmelanoma skin cancer. Br J Dermatol 176(2):498–502

    Article  CAS  PubMed  Google Scholar 

  19. Cohen PR, Kato S, Goodman AM, Ikeda S, Kurzrock R (2017) Appearance of New Cutaneous Superficial Basal Cell Carcinomas during successful nivolumab treatment of refractory metastatic disease: implications for immunotherapy in early versus late disease. Int J Mol Sci. https://doi.org/10.3390/ijms18081663

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fischer S, Ali OH, Jochum W, Kluckert T, Flatz L, Siano M (2018) Anti-PD-1 therapy leads to near-complete remission in a patient with metastatic basal cell carcinoma. Oncol Res Treat 41(6):391–394

    Article  CAS  PubMed  Google Scholar 

  21. Cannon JGD, Russell JS, Kim J, Chang ALS (2018) A case of metastatic basal cell carcinoma treated with continuous PD-1 inhibitor exposure even after subsequent initiation of radiotherapy and surgery. JAAD Case Rep 4(3):248–250

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chang ALS, Tran DC, Cannon JGD, Li S, Jeng M, Patel R et al (2019) Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study. J Am Acad Dermatol 80(2):564–566

    Article  PubMed  Google Scholar 

  23. Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Kaatz M et al (2021) Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol 22(6):848–857

    Article  CAS  PubMed  Google Scholar 

  24. Dumann K, Artz N, Ziemer M (2021) Complete remission of basal cell carcinoma following treatment with cemiplimab after 2 years. JAMA Dermatol 157(8):1004

    Article  PubMed  Google Scholar 

  25. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sunshine J, Taube JM (2015) PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 23:32–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH et al (2014) 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 20(19):5064–5074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028

    Article  PubMed  Google Scholar 

  30. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515(7528):558–562

    Article  CAS  PubMed  Google Scholar 

  32. Research C for DE and. Approved Drugs - FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma [Internet]. Disponible en: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm622251.htm

  33. Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B et al (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol 24(5):235–251

    Article  PubMed  PubMed Central  Google Scholar 

  34. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271

    Article  CAS  PubMed  Google Scholar 

  35. Daud AI, Hamid O, Ribas A, Hodi FS, Hwu W-J, Kefford R et al (2014) Abstract CT104: Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): correlation of tumor PD-L1 expression with outcome. Cancer Res 74(19 Supplement):CT104

    Article  Google Scholar 

  36. Daud AI, Wolchok JD, Robert C, Hwu W-J, Weber JS, Ribas A et al (2016) Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34(34):4102–4109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cameron MC, Lee E, Hibler BP, Giordano CN, Barker CA, Mori S et al (2019) Basal cell carcinoma: contemporary approaches to diagnosis, treatment, and prevention. J Am Acad Dermatol 80(2):321–339

    Article  PubMed  Google Scholar 

  38. Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen JS, Berg D et al (2016) Basal cell skin cancer, version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw JNCCN. 14(5):574–597

    Article  PubMed  Google Scholar 

  39. Basal_Cell_Skin_Cancer.pdf [Internet]. [citado 11 de marzo de 2019]. Disponible en: https://oncolife.com.ua/doc/nccn/Basal_Cell_Skin_Cancer.pdf

  40. Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348(6237):880–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964

    Article  CAS  PubMed  Google Scholar 

  42. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kitano Y, Yamashita Y-I, Nakao Y, Itoyama R, Yusa T, Umezaki N et al (2020) Clinical significance of PD-L1 expression in both cancer and stroma cells of cholangiocarcinoma patients. Ann Surg Oncol 27(2):599–607

    Article  PubMed  Google Scholar 

  44. Zhai Q, Fan J, Lin Q, Liu X, Li J, Hong R et al (2019) Tumor stromal type is associated with stromal PD-L1 expression and predicts outcomes in breast cancer. PLoS ONE 14(10):e0223325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li X, Wetherilt CS, Krishnamurti U, Yang J, Ma Y, Styblo TM et al (2016) Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. Am J Clin Pathol 146(4):496–502

    Article  CAS  PubMed  Google Scholar 

  46. Wyss J, Dislich B, Koelzer VH, Galván JA, Dawson H, Hädrich M et al (2019) Stromal PD-1/PD-L1 expression predicts outcome in colon cancer patients. Clin Colorectal Cancer 18(1):e20-38

    Article  PubMed  Google Scholar 

  47. Madore J, Vilain RE, Menzies AM, Kakavand H, Wilmott JS, Hyman J et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28(3):245–253

    Article  CAS  PubMed  Google Scholar 

  48. Slater NA, Googe PB (2016) PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J Cutan Pathol 43(8):663–670

    Article  PubMed  Google Scholar 

  49. Kaunitz GJ, Cottrell TR, Lilo M, Muthappan V, Esandrio J, Berry S et al (2017) Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Investig J Tech Methods Pathol 97(9):1063–1071

    Article  CAS  Google Scholar 

  50. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ (2018) PD-L1. J Clin Pathol 71(3):189–194

    Article  PubMed  Google Scholar 

  51. Chang J, Zhu GA, Cheung C, Li S, Kim J, Chang ALS (2017) Association between programmed death ligand 1 expression in patients with basal cell carcinomas and the number of treatment modalities. JAMA Dermatol 153(4):285–290

    Article  PubMed  Google Scholar 

  52. Yamashita K, Iwatsuki M, Harada K, Eto K, Hiyoshi Y, Ishimoto T et al (2020) Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer 23(1):95–104

    Article  CAS  PubMed  Google Scholar 

  53. Kulangara K, Zhang N, Corigliano E, Guerrero L, Waldroup S, Jaiswal D et al (2019) Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch Pathol Lab Med 143(3):330–337

    Article  CAS  PubMed  Google Scholar 

  54. Kim S-H, Go S-I, Song DH, Park SW, Kim HR, Jang I et al (2019) Prognostic impact of CD8 and programmed death-ligand 1 expression in patients with resectable non-small cell lung cancer. Br J Cancer 120(5):547–554

    Article  PubMed  PubMed Central  Google Scholar 

  55. Tian C, Lu S, Fan Q, Zhang W, Jiao S, Zhao X et al (2015) Prognostic significance of tumor-infiltrating CD8+ or CD3+ T lymphocytes and interleukin-2 expression in radically resected non-small cell lung cancer. Chin Med J (Engl) 128(1):105–110

    Article  CAS  Google Scholar 

  56. Orhan A, Vogelsang RP, Andersen MB, Madsen MT, Hölmich ER, Raskov H et al (1990) The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis. Eur J Cancer Oxf Engl 2020(132):71–84

    Google Scholar 

  57. Omland SH, Nielsen PS, Gjerdrum LMR, Gniadecki R (2016) Immunosuppressive environment in basal cell carcinoma: the role of regulatory T cells. Acta Derm Venereol 96(7):917–921

    Article  CAS  PubMed  Google Scholar 

  58. Del Puerto C, Navarrete-Dechent C, Molgó M, Camargo CA, Borzutzky A, González S (2018) Immunohistochemical expression of vitamin D receptor in melanocytic naevi and cutaneous melanoma: a case-control study. Br J Dermatol 179(1):95–100

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

None, only Department of Dermatology internal research funds. None of the authors had any relationship with financial entities involved in producing IHC or anti PD-1/PD-L1 drugs.

Author information

Author notes

  1. Sergio Gonzalez, Pablo Uribe and Cristian Navarrete-Dechent shared senior authorship.

Authors and Affiliations

  1. Department of Dermatology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Diagonal Paraguay 362, 6th Floor, 8330077, Santiago, Chile

    Matias Gompertz-Mattar, Juan Perales, Pablo Uribe & Cristian Navarrete-Dechent

  2. Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Aditi Sahu

  3. Department of Medical Oncology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile

    Sebastián Mondaca

  4. Department of Pathology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile

    Sergio Gonzalez

  5. Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile

    Sebastián Mondaca, Pablo Uribe & Cristian Navarrete-Dechent

Authors
  1. Matias Gompertz-Mattar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan Perales
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aditi Sahu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sebastián Mondaca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergio Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pablo Uribe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cristian Navarrete-Dechent
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MG-M, JP, AS, SM, SG, PU, CN-D: Acquisition, analysis and interpretation of data, Drafting and revising the article, Final approval of the version to be published.

Corresponding author

Correspondence to Cristian Navarrete-Dechent.

Ethics declarations

Conflict of interest

The author(s) does not declare any conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gompertz-Mattar, M., Perales, J., Sahu, A. et al. Differential expression of programmed cell death ligand 1 (PD-L1) and inflammatory cells in basal cell carcinoma subtypes. Arch Dermatol Res 314, 777–786 (2022). https://doi.org/10.1007/s00403-021-02289-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-021-02289-w

Keywords

Search

Navigation