Abstract
<h3>Background:</h3> In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20–30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. <h3>Methods:</h3> In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, in order to characterize markers of lesion progression. <h3>Results:</h3> Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of a combination of tissue residency markers, heat shock proteins, tumor suppressor genes and chemokine receptors in the malignant clone. By contrast, collateral benign infiltrating immune cells within the lesions did not show consistent changes at the mRNA level. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a mechanism across MF subtypes. Markers of disease progression were reverted upon successful topical treatment with chlormethine. <h3>Conclusions:</h3> Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.
Highlights
Primary cutaneous T-cell lymphomas (CTCL) comprise a clinically and biologically heterogeneous group of malignancies arising from the clonal proliferation of skinhoming or skin-resident T cells [1]
Single‐cell RNA‐seq mapping mycosis fungoides skin lesions We investigated three adult CTCL patients (MF309, MF311 and MF312, Table 1) suffering from advancedstage MF, previously confirmed by conventional histopathology (Fig. 1 A)
We discovered six genes to be downregulated in all patients in plaque/tumor vs. patch lesions, namely the chemokine receptor CXCR4, the skin residency marker CD69, the heat shock protein HSPA1A, the anti-inflammatory mediator tristetraprolin, the interleukin-7 receptor interleukin 7 receptor (IL7R), and the thioredoxin-interacting protein TXNIP (Fig. 3 H, Table S3)
Summary
Primary cutaneous T-cell lymphomas (CTCL) comprise a clinically and biologically heterogeneous group of malignancies arising from the clonal proliferation of skinhoming or skin-resident T cells [1]. Results were compared with early-stage disease, clinically unaffected (nonlesional) MF skin as well as control skin from healthy individuals. By using single-cell RNA sequencing (scRNA-seq) combined with T-cell receptor (TCR) sequencing, our data reveal a characteristic panel of six markers to be consistently downregulated in clonally expanded T cells of advancing MF lesions, as opposed to patches from indolent early-stage disease or clinically unaffected skin. In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Factors contributing to this switch from indolent to aggressive disease are only insufficiently understood
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