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

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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.

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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

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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.

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).

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Author notes

  1. Cyrill Géraud and Moritz Felcht contributed equally.

Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany

    Corinne Bauer, Viktor Umansky, Jochen Utikal, Sergij Goerdt, Cyrill Géraud & Moritz Felcht

  2. European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Corinne Bauer, Ashik Ahmed Abdul Pari, Hellmut G. Augustin, Sergij Goerdt, Cyrill Géraud & Moritz Felcht

  3. Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany

    Corinne Bauer, Ashik Ahmed Abdul Pari, Hellmut G. Augustin & Moritz Felcht

  4. German Cancer Consortium, Heidelberg, Germany

    Corinne Bauer, Ashik Ahmed Abdul Pari, Hellmut G. Augustin & Moritz Felcht

  5. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    Ashik Ahmed Abdul Pari

  6. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Viktor Umansky & Jochen Utikal

  7. Genetics of Skin Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Petra Boukamp

  8. IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Petra Boukamp

  9. Section of Molecular and Clinical Dermatology, Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Cyrill Géraud

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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.

Corresponding author

Correspondence to Moritz Felcht.

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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.

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Bauer, C., Abdul Pari, A.A., Umansky, V. et al. T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin. Cancer Immunol Immunother 67, 1147–1157 (2018). https://doi.org/10.1007/s00262-018-2171-7

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