Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics

Lukas Peiffer; Thilo Gambichler; Terkild B Buus; Kai Horny; Jan Gravemeyer; Frauke Furtmann; Ivelina Spassova; Linda Kubat; Laura Susok; René Stranzenbach; Nalini Srinivas; Niels Ødum; Jürgen C Becker

doi:10.3389/fonc.2023.1090592

Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics

Front Oncol. 2023 Jan 25:13:1090592. doi: 10.3389/fonc.2023.1090592. eCollection 2023.

Authors

Lukas Peiffer^{1

2

3}, Thilo Gambichler⁴, Terkild B Buus³, Kai Horny^{1

2}, Jan Gravemeyer^{1

2}, Frauke Furtmann⁵, Ivelina Spassova^{1

5}, Linda Kubat^{1

5}, Laura Susok⁴, René Stranzenbach⁴, Nalini Srinivas^{1

2}, Niels Ødum³, Jürgen C Becker^{1

2

5}

Affiliations

¹ Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany.
² Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
³ Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
⁴ Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Ruhr-University, Bochum, Germany.
⁵ Department of Dermatology, University of Essen, Essen, Germany.

Abstract

Background: Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma.

Objective: To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS.

Methods: We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq).

Results: We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as CCR7, IL7R and CD27. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including GZMB and NKG7. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of TXNIP, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells.

Conclusions: Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.

Keywords: Sézary syndrome; cutaneous T cell lymphoma; inflammation; malignant T cells; reactive T cells; scRNAseq.

Grants and funding

This study was supported by the Deutsches Konsortium für Translationale Krebsforschung (DKTK, ED03) and LP received a scholarship from the University of Copenhagen. This research received financial support by the Open Access Publication Funds of the Ruhr-Universität Bochum.