Single-cell RNA sequencing comparison of CD4+, CD8+ and TCR-γδ+ cutaneous T-cell lymphomas reveals subset-specific molecular phenotypes.

in The British journal of dermatology by Sumanth Chennareddy, Katharina Rindler, John R Ruggiero, Natalia Alkon, Emry R Cohenour, Sophia Tran, Wolfgang Weninger, Johannes Griss, Constanze Jonak, Patrick M Brunner

TLDR

  • The study looked at different types of skin cancer called CTCL and compared their molecular characteristics. They found that TCR-γ/δ+MF and Berti's lymphoma had similar clustering patterns, increased expression of cytotoxic markers, and a more tissue-resident phenotype compared to CD4+MF lesions. CD4+MF lesions showed strong type 2 immune activation and upregulation of keratinocyte hyperactivation markers, while Berti's lymphoma was more skewed towards type 1 immune responses and did not show upregulation of these markers. The study highlights the importance of understanding the molecular characteristics of different CTCL subtypes to improve diagnosis, prognosis, and treatment.

Abstract

Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4, CD8 or TCR-γδ phenotype, but their individual impact on tumor biology and skin lesion formation remains ill-defined. To perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γ/δ+ CTCL lesions. We performed scRNA-seq of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti's lymphoma). Malignant clones of TCR-γ/δ+MF and Berti's lymphoma showed similar clustering patterns distinct from CD4+MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA, and GZMM. Only advanced-stage CD4+MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γ/δ+MF and Berti's lymphoma harbored a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+MF and TCR-γ/δ+MF skin lesions harbored strong type 2 immune activation across myeloid cells, while Berti's lymphoma was more skewed towards type 1 immune responses. Both CD4+MF and TCR-γ/δ+MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100As and KRT16 genes. This increase was entirely absent in Berti's lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumor cells, that could contribute to the formation of the typical ulcero-necrotic lesions within this entity. Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.

Overview

  • The study aims to compare the molecular characteristics of CD4+ and CD8+ CTCL lesions. The authors performed scRNA-seq on 18 skin biopsies from patients with classic CD4+ advanced-stage mycosis fungoides (MF), TCR-γ/δ+MF, and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti's lymphoma).
  • The study compares the clustering patterns, expression of cytotoxic markers, central memory T-cell markers, tissue-resident phenotype, type 1 and type 2 immune responses, and keratinocyte hyperactivation markers in CD4+ and CD8+ CTCL lesions. The authors found that TCR-γ/δ+MF and Berti's lymphoma showed similar clustering patterns, increased expression of cytotoxic markers, and a more tissue-resident phenotype. CD4+MF lesions showed strong type 2 immune activation and upregulation of keratinocyte hyperactivation markers, while Berti's lymphoma was more skewed towards type 1 immune responses and did not show upregulation of these markers. The study reveals specific molecular patterns associated with distinct CTCL subtypes.

Comparative Analysis & Findings

  • The study found that TCR-γ/δ+MF and Berti's lymphoma showed similar clustering patterns, increased expression of cytotoxic markers, and a more tissue-resident phenotype compared to CD4+MF lesions. CD4+MF lesions showed strong type 2 immune activation and upregulation of keratinocyte hyperactivation markers, while Berti's lymphoma was more skewed towards type 1 immune responses and did not show upregulation of these markers. The study reveals specific molecular patterns associated with distinct CTCL subtypes.

Implications and Future Directions

  • The study highlights the importance of understanding the molecular characteristics of different CTCL subtypes to improve diagnosis, prognosis, and treatment. The authors suggest that further research is needed to validate these findings and identify potential therapeutic targets for each subtype. Additionally, the study highlights the potential role of keratinocyte hyperactivation markers in the pathogenesis of CTCL and the importance of considering the immune response in the development of targeted therapies.
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