Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma

Background: 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. Methods: 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. Results: 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. Conclusions: 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. 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. 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. 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. 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.