Advertisement

Cancer Immunology, Immunotherapy

, Volume 67, Issue 7, pp 1147–1157 | Cite as

T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin

  • Corinne Bauer
  • Ashik Ahmed Abdul Pari
  • Viktor Umansky
  • Jochen Utikal
  • Petra Boukamp
  • Hellmut G. Augustin
  • Sergij Goerdt
  • Cyrill Géraud
  • Moritz Felcht
Original Article

Abstract

Background

T-lymphocytes are involved in tumor progression and regression. Actinic keratoses (AK) are atypical proliferations of keratinocytes of the skin. Some AK progress into invasive cutaneous squamous cell carcinomas (cSCC). Keratoacanthomas (KA) are either classified as a cSCC subtype or a benign tumor with histologic resemblance to well-differentiated cSCC as it is supposed to regress spontaneously. In contrast, cSCC represent malignant tumors that may metastasize.

Objectives

To compare the T-lymphocyte profiles of AK, KA and cSCC in relation to PD-L1 expression.

Methods

Tissue micro-arrays of 103 cases of AK, 43 cases of KA and 106 cases of cSCC were stained by immunohistochemistry for E-cadherin, CD3, CD4, CD8, FOXp3, and the receptor–ligand pair PD-1/PD-L1. Immunohistological scores were computationally determined to assess PD-L1 expression as well as the expression profiles of T-lymphocytes.

Results

AK had lower numbers of CD3+ and PD-1+ cells compared to KA and lower numbers of CD3+, CD8+ and PD-1+ cells in comparison with cSCC. KA showed significantly higher numbers of CD4+ and FOXp3+ cells as well as lower numbers of CD8+ cells in comparison with invasive cSCC. cSCC expressed significantly more PD-L1 in comparison with AK and KA. Among cSCC PD-L1 expression was higher in moderately and poorly-differentiated cSCC than in well-differentiated cSCC. Increased PD-L1 expression also correlated with increased numbers of CD4+, CD8+ and FOXp3+ cells in cSCC.

Conclusions

Tumor-associated T-lymphocyte infiltrates showed significant differences between AK, KA and invasive cSCC. PD-L1 expression correlated with invasion of T-cell infiltrates in invasive cSCC.

Keywords

PD-1 PD-L1 FOXp3 Tumor microenvironment 

Abbreviations

AK

Actinic keratosis

cSCC

Cutaneous squamous cell carcinoma

KA

Keratoacanthoma

NCT

National Center of Tumor Diseases

OTR

Organ transplant recipients

ROI

Region of interest

TGF-β

Transforming growth factor beta

TMA

Tissue micro-array

Notes

Acknowledgements

We like to thank Dr. Damir Krunic from the Imaging Core Facility of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ, Germany) as well as Helmut Hübers for technical support with image analysis. This research was supported by the tissue bank of the NCT (Heidelberg, Germany) by staining the skin tumor samples.

Author contributions

Study conception and design were done by Corinne Bauer, Ashik Ahmed Abdul Pari, Viktor Umansky, Petra Boukamp, Cyrill Géraud and Moritz Felcht. Corinne Bauer, Ashik Ahmed Abdul Pari, Cyrill Géraud and Moritz Felcht are responsible for the integrity of acquired data. Statistical analysis was performed by Corinne Bauer, Ashik Ahmed Abdul Pari, Cyrill Géraud and Moritz Felcht. Corinne Bauer, Ashik Ahmed Abdul Pari, Viktor Umansky, Petra Boukamp, Cyrill Géraud, Moritz Felcht prepared the initial manuscript. Corinne Bauer, Ashik Ahmed Abdul Pari, Viktor Umansky, Jochen Utikal, Petra Boukamp, Hellmut G. Augustin, Sergij Goerdt, Cyrill Géraud and Moritz Felcht made substantial contributions to data analysis and interpretation of results, rewriting of the manuscript, review and approval.

Funding

This work was supported by Grants from the Deutsche Forschungsgemeinschaft (German Research Council) [Förderprojekt Nr. FE 1282/2-1 (Moritz Felcht) and GRK2099/RTG2099 “Hallmarks of Skin Cancer” (to Viktor Umansky, Jochen Utikal, Hellmut G. Augustin, Sergij Goerdt, Cyrill Géraud and Moritz Felcht)] and partially supported by the Federal Ministry for Research and Education (Bundesmininsterium für Bildung und Forschung, BMBF) (FKZ 02NUK036A to Petra Boukamp).

Compliance with ethical standards

Conflict of interest

Moritz Felcht received travel and congress participation funding by TEVA company, honoraria as an advisory board member of AbbVie Ltd. and lecture fees by Periderm GmbH and Mibe Vertrieb GmbH. All other authors declare no conflict of interest.

Ethical standards

The study was performed with archived paraffin-embedded tissue samples. The study was approved by the ethical committee II of Heidelberg University (2014-835R-MA).

Informed consent

Informed consent by individual patients cannot be given, as the study only included paraffin-embedded archived tissue. With the approval of the ethical committee informed consent was not required as all patient data were anonymized.

Supplementary material

262_2018_2171_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1455 KB)

References

  1. 1.
    Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA (2013) Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol 149:541–547.  https://doi.org/10.1001/jamadermatol.2013.2139 CrossRefPubMedGoogle Scholar
  2. 2.
    Karia PS, Han J, Schmults CD (2013) Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 68:957–966.  https://doi.org/10.1016/j.jaad.2012.11.037 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lamberg AL, Solvsten H, Lei U et al (2016) The Danish nonmelanoma skin cancer dermatology database. Clin Epidemiol 8:633–636.  https://doi.org/10.2147/CLEP.S99464 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rogers HW, Weinstock MA, Feldman SR, Coldiron BM (2015) Incidence estimate of nonmelanoma skin cancer (Keratinocyte Carcinomas) in the US population, 2012. JAMA Dermatol 151:1081–1086.  https://doi.org/10.1001/jamadermatol.2015.1187 CrossRefPubMedGoogle Scholar
  5. 5.
    Lobeck A, Weiss C, Orouji A et al. (2017) Single center analysis of the dermatosurgical patient cohort of a tumor center in Germany. Hautarzt 68:377–384.  https://doi.org/10.1007/s00105-017-3951-2 CrossRefPubMedGoogle Scholar
  6. 6.
    Thompson AK, Kelley BF, Prokop LJ, Murad MH, Baum CL (2016) Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis. JAMA Dermatol 152:419–428.  https://doi.org/10.1001/jamadermatol.2015.4994 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Burnworth B, Popp S, Stark HJ, Steinkraus V, Brocker EB, Hartschuh W, Birek C, Boukamp P (2006) Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation. Oncogene 25:4399–4412.  https://doi.org/10.1038/sj.onc.1209474 CrossRefPubMedGoogle Scholar
  8. 8.
    Gleich T, Chiticariu E, Huber M, Hohl D (2016) Keratoacanthoma: a distinct entity? Exp Dermatol 25:85–91.  https://doi.org/10.1111/exd.12880 CrossRefPubMedGoogle Scholar
  9. 9.
    Kwiek B, Schwartz RA (2016) Keratoacanthoma (KA): an update and review. J Am Acad Dermatol 74:1220–1233.  https://doi.org/10.1016/j.jaad.2015.11.033 CrossRefPubMedGoogle Scholar
  10. 10.
    Selmer J, Skov T, Spelman L, Weedon D (2016) Squamous cell carcinoma and keratoacanthomas are biologically distinct and can be diagnosed by light microscopy: a review. Histopathology 69:535–541.  https://doi.org/10.1111/his.13018 CrossRefPubMedGoogle Scholar
  11. 11.
    Stockfleth E (2017) The importance of treating the field in actinic keratosis. J Eur Acad Dermatol Venereol 31(Suppl 2):8–11.  https://doi.org/10.1111/jdv.14092 CrossRefPubMedGoogle Scholar
  12. 12.
    Fernandez Figueras MT (2017) From actinic keratosis to squamous cell carcinoma: pathophysiology revisited. J Eur Acad Dermatol Venereol 31(Suppl 2):5–7.  https://doi.org/10.1111/jdv.14151 CrossRefPubMedGoogle Scholar
  13. 13.
    Cassarino DS, Derienzo DP, Barr RJ (2006) Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification—part two. J Cutan Pathol 33:261–279.  https://doi.org/10.1111/j.0303-6987.2006.00516.x CrossRefPubMedGoogle Scholar
  14. 14.
    Ra SH, Li X, Binder S (2011) Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin. Mod Pathol 24:963–973.  https://doi.org/10.1038/modpathol.2011.39 CrossRefPubMedGoogle Scholar
  15. 15.
    Martincorena I, Roshan A, Gerstung M et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348:880–886.  https://doi.org/10.1126/science.aaa6806 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Siegel JA, Korgavkar K, Weinstock MA (2017) Current perspective on actinic keratosis: a review. Br J Dermatol 177:350–358.  https://doi.org/10.1111/bjd.14852 CrossRefPubMedGoogle Scholar
  17. 17.
    Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271.  https://doi.org/10.1146/annurev-immunol-031210-101324 CrossRefPubMedGoogle Scholar
  18. 18.
    Yanofsky VR, Mitsui H, Felsen D, Carucci JA (2013) Understanding dendritic cells and their role in cutaneous carcinoma and cancer immunotherapy. Clin Dev Immunol. 2013:624123.  https://doi.org/10.1155/2013/624123 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268–276.  https://doi.org/10.1016/j.coi.2013.02.009 CrossRefPubMedGoogle Scholar
  20. 20.
    Szturz P, Vermorken JB (2017) Immunotherapy in head and neck cancer: aiming at EXTREME precision. BMC Med 15:110.  https://doi.org/10.1186/s12916-017-0879-4 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bluth MJ, Zaba LC, Moussai D et al (2009) Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation. J Invest Dermatol 129:2451–2462.  https://doi.org/10.1038/jid.2009.96 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kambayashi Y, Fujimura T, Aiba S (2013) Comparison of immunosuppressive and immunomodulatory cells in keratoacanthoma and cutaneous squamous cell carcinoma. Acta Derm Venereol 93:663–668.  https://doi.org/10.2340/00015555-1597 CrossRefPubMedGoogle Scholar
  23. 23.
    Lai C, August S, Behar R, Polak M, Ardern-Jones M, Theaker J, Al-Shamkhani A, Healy E (2015) Characteristics of immunosuppressive regulatory T cells in cutaneous squamous cell carcinomas and role in metastasis. Lancet 385 (Suppl 1):S59.  https://doi.org/10.1016/S0140-6736(15)60374-9 CrossRefPubMedGoogle Scholar
  24. 24.
    Mishra AK, Kadoishi T, Wang X, Driver E, Chen Z, Wang XJ, Wang JH (2016) Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors. Oncotarget 7:81341–81356.  https://doi.org/10.18632/oncotarget.13228 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gambichler T, Gnielka M, Ruddel I, Stockfleth E, Stucker M, Schmitz L (2017) Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma. Cancer Immunol Immunother 66:1199–1204.  https://doi.org/10.1007/s00262-017-2015-x CrossRefPubMedGoogle Scholar
  26. 26.
    Ayers M, Lunceford J, Nebozhyn M et al (2017) IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940.  https://doi.org/10.1172/JCI91190 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    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 188:420–429.  https://doi.org/10.1111/cei.12921 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Stevenson ML, Wang CQ, Abikhair M, Roudiani N, Felsen D, Krueger JG, Pavlick AC, Carucci JA (2017) Expression of programmed cell death ligand in cutaneous squamous cell carcinoma and treatment of locally advanced disease with pembrolizumab. JAMA Dermatol 153:299–303.  https://doi.org/10.1001/jamadermatol.2016.5118 CrossRefPubMedGoogle Scholar
  29. 29.
    Linedale R, Schmidt C, King BT, Ganko AG, Simpson F, Panizza BJ, Leggatt GR (2017) Elevated frequencies of CD8 T cells expressing PD-1, CTLA-4 and Tim-3 within tumour from perineural squamous cell carcinoma patients. PLoS One 12:e0175755.  https://doi.org/10.1371/journal.pone.0175755 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mittal A, Colegio OR (2017) Skin cancers in organ transplant recipients. Am J Transplant 17:2509–2530.  https://doi.org/10.1111/ajt.14382 CrossRefPubMedGoogle Scholar
  31. 31.
    Rosen RH, Gupta AK, Tyring SK (2012) Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol 66:486–493.  https://doi.org/10.1016/j.jaad.2010.12.038 CrossRefPubMedGoogle Scholar
  32. 32.
    Walter A, Schafer M, Cecconi V et al (2013) Aldara activates TLR7-independent immune defence. Nat Commun 4:1560.  https://doi.org/10.1038/ncomms2566 CrossRefPubMedGoogle Scholar
  33. 33.
    Speiser DE, Ho PC, Verdeil G (2016) Regulatory circuits of T cell function in cancer. Nat Rev Immunol 16:599–611.  https://doi.org/10.1038/nri.2016.80 CrossRefPubMedGoogle Scholar
  34. 34.
    Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116.  https://doi.org/10.1126/scitranslmed.3006504 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264.  https://doi.org/10.1038/nrc3239 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022.  https://doi.org/10.1038/ni.2703 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212–1218.  https://doi.org/10.1038/ni.2762 CrossRefPubMedGoogle Scholar
  38. 38.
    Boussiotis VA, Chatterjee P, Li L (2014) Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J 20:265–271.  https://doi.org/10.1097/PPO.0000000000000059 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Weedon D (2009) Skin tumors. Weedon’s skin pathology. 3rd edn. London: Churchill Livingstone, pp 702–708. ISBN 9780702047749Google Scholar
  40. 40.
    Felcht M, Heck M, Weiss C et al. (2012) Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells. Br J Dermatol 167:348–358.  https://doi.org/10.1111/j.1365-2133.2012.10987.x CrossRefPubMedGoogle Scholar
  41. 41.
    Slater NA, Googe PB (2016) PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J Cutan Pathol 43:663–670.  https://doi.org/10.1111/cup.12728 CrossRefPubMedGoogle Scholar
  42. 42.
    Garcia-Pedrero JM, Martinez-Camblor P, Diaz-Coto S, Munguia-Calzada P, Vallina-Alvarez A, Vazquez-Lopez F, Rodrigo JP, Santos-Juanes J (2017) Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. J Am Acad Dermatol 77:527–533.  https://doi.org/10.1016/j.jaad.2017.05.047 CrossRefPubMedGoogle Scholar
  43. 43.
    Roper E, Lum T, Palme CE, Ashford B, Ch’ng S, Ranson M, Boyer M, Clark J, Gupta R (2017) PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma. Pathology 49:499–505.  https://doi.org/10.1016/j.pathol.2017.04.004 CrossRefPubMedGoogle Scholar
  44. 44.
    Awad MM, Jones RE, Liu H et al (2016) Cytotoxic T cells in PD-L1-positive malignant pleural mesotheliomas are counterbalanced by distinct immunosuppressive factors. Cancer Immunol Res 4:1038–1048.  https://doi.org/10.1158/2326-6066.CIR-16-0171 CrossRefPubMedGoogle Scholar
  45. 45.
    Li Z, Dong P, Ren M, Song Y, Qian X, Yang Y, Li S, Zhang X, Liu F (2016) PD-L1 expression is associated with tumor FOXP3(+) regulatory T-cell infiltration of breast cancer and poor prognosis of patient. J Cancer 7:784–793.  https://doi.org/10.7150/jca.14549 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Thompson ED, Taube JM, Asch-Kendrick RJ et al (2017) PD-L1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast. Mod Pathol 30:1551–1560.  https://doi.org/10.1038/modpathol.2017.79 CrossRefPubMedGoogle Scholar
  47. 47.
    Stasikowska-Kanicka O, Wagrowska-Danilewicz M, Danilewicz M (2017) Immunohistochemical analysis of Foxp3+, CD4+, CD8 + cell infiltrates and PD-L1 in oral squamous cell carcinoma. Pathol Oncol Res doi.  https://doi.org/10.1007/s12253-017-0270-y CrossRefGoogle Scholar
  48. 48.
    Cunningham TJ, Tabacchi M, Eliane JP et al (2017) Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 127:106–116.  https://doi.org/10.1172/JCI89820 CrossRefPubMedGoogle Scholar
  49. 49.
    Lai C, August S, Albibas A et al (2016) OX40 + regulatory T cells in cutaneous squamous cell carcinoma suppress effector T-cell responses and associate with metastatic potential. Clin Cancer Res 22:4236–4248.  https://doi.org/10.1158/1078-0432.CCR-15-2614 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Crespo E, Fernandez L, Lucia M et al (2017) Effector antitumor and regulatory T cell responses influence the development of nonmelanoma skin cancer in kidney transplant patients. Transplantation 101:2102–2110.  https://doi.org/10.1097/TP.0000000000001759 CrossRefPubMedGoogle Scholar
  51. 51.
    Tanaka A, Sakaguchi S (2017) Regulatory T cells in cancer immunotherapy. Cell Res 27:109–118.  https://doi.org/10.1038/cr.2016.151 CrossRefPubMedGoogle Scholar
  52. 52.
    Azzimonti B, Zavattaro E, Provasi M, Vidali M, Conca A, Catalano E, Rimondini L, Colombo E, Valente G (2015) Intense Foxp3+ CD25+ regulatory T-cell infiltration is associated with high-grade cutaneous squamous cell carcinoma and counterbalanced by CD8+/Foxp3+ CD25+ ratio. Br J Dermatol 172:64–73.  https://doi.org/10.1111/bjd.13172 CrossRefPubMedGoogle Scholar
  53. 53.
    Baas M, Besancon A, Goncalves T et al (2016) TGFbeta-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance. Elife 5:e08133.  https://doi.org/10.7554/eLife.08133 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Goudie DR, D’Alessandro M, Merriman B et al (2011) Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genet 43:365–369.  https://doi.org/10.1038/ng.780 CrossRefPubMedGoogle Scholar
  55. 55.
    Lacouture ME, Morris JC, Lawrence DP et al (2015) Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor beta by the monoclonal antibody fresolimumab (GC1008). Cancer Immunol Immunother 64:437–446.  https://doi.org/10.1007/s00262-015-1653-0 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Corinne Bauer
    • 1
    • 2
    • 3
    • 4
  • Ashik Ahmed Abdul Pari
    • 2
    • 3
    • 4
    • 5
  • Viktor Umansky
    • 1
    • 6
  • Jochen Utikal
    • 1
    • 6
  • Petra Boukamp
    • 7
    • 8
  • Hellmut G. Augustin
    • 2
    • 3
    • 4
  • Sergij Goerdt
    • 1
    • 2
  • Cyrill Géraud
    • 1
    • 2
    • 9
  • Moritz Felcht
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty MannheimHeidelberg University and Centre of Excellence of Dermatology of Baden-WürttembergMannheimGermany
  2. 2.European Center for Angioscience, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  3. 3.Division of Vascular Oncology and MetastasisGerman Cancer Research Center (DKFZ-ZMBH Alliance)HeidelbergGermany
  4. 4.German Cancer ConsortiumHeidelbergGermany
  5. 5.Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
  6. 6.Skin Cancer UnitGerman Cancer Research Center (DKFZ)HeidelbergGermany
  7. 7.Genetics of Skin CarcinogenesisGerman Cancer Research Center (DKFZ)HeidelbergGermany
  8. 8.IUF-Leibniz Research Institute for Environmental MedicineDüsseldorfGermany
  9. 9.Section of Molecular and Clinical Dermatology, Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany

Personalised recommendations