070 Comprehensive single-cell analysis of Sézary syndrome reveals novel expression and therapeutic biomarkers

Abstract

Cutaneous T cell lymphomas (CTCL) are a group of malignancies thought to derive from a clonal proliferation of skin-tropic T cells. Diagnosis is often delayed several years due to variations in presentation and lack of definitive biomarkers, which result in missed early intervention opportunities that may prevent disease progression. In the setting of more aggressive forms of CTCL, most treatments can initially decrease the tumor burden, but often ultimately fail to prevent the selective outgrowth of a resistant population. The lack of effective therapies is due in part to an incomplete understanding of tumor biology. Using single-cell mRNA and adaptive immune receptor sequencing of peripheral blood immune cells in SS, transcriptomic variations were quantified of almost 50,000 malignant and nonmalignant T cells across six SS patients. Within the population of single cells, we identified both quiescent and proliferative populations across multiple patients, and were able to newly identify a large number of genes associated with malignancy. Furthermore, in a single patient, we characterized differences in cell populations comparing malignant T cells after disease progression in the setting of treatment with histone deacetylase inhibition (HDACi) and photopheresis. HDACi therapy led to new transcriptional profiles in a subset of SS cells, characterized by the increased expression of the transcriptional factor FOXP3. These data are critical in defining a compendium of gene expression profiles and intratumoral heterogeneity in SS and CTCL, which are pivotal in our understanding of CTCL biology and in the development of targeted treatments.