Combined High-Throughput Approaches Reveal the Signals Driven by Skin and Blood Environments and Define the Tumor Heterogeneity in Sézary Syndrome

Abstract

Sézary syndrome (SS) is an aggressive variant of cutaneous t-cell lymphoma characterized by the accumulation of neoplastic CD4+ lymphocytes—the SS cells—mainly in blood, lymph nodes, and skin. The tumor spread pattern of SS makes this lymphoma a unique model of disease that allows a concurrent blood and skin sampling for analysis. This review summarizes the recent studies highlighting the transcriptional programs triggered by the crosstalk between SS cells and blood–skin microenvironments. Emerging data proved that skin-derived SS cells show consistently higher activation/proliferation rates, mainly driven by T-cell receptor signaling with respect to matched blood SS cells that instead appear quiescent. Biochemical analyses also demonstrated an hyperactivation of PI3K/AKT/mTOR, a targetable pathway by multiple inhibitors currently in clinical trials, in skin SS cells compared with a paired blood counterpart. These results indicated that active and quiescent SS cells coexist in this lymphoma, and that they could be respectively treated with different therapeutics. Finally, this review underlines the more recent discoveries into the heterogeneity of circulating SS cells, highlighting a series of novel markers that could improve the diagnosis and that represent novel therapeutic targets (GPR15, PTPN13, KLRB1, and ITGB1) as well as new genetic markers (PD-1 and CD39) able to stratify SS patients for disease aggressiveness.

Single-cell analyses reveal novel molecular signatures and pathogenesis in cutaneous T cell lymphoma

“…Single-cell profiling of skin biopsies from advanced mycosis fungoides (MF)/SS patients has revealed a common gene expression signature ( PCNA , ATP5C1 , and NUSPA1 ) with important implications for diagnosis and treatment of CTCL, even though only a few tumor-specific marker genes were shared in different samples [ 10 ]. However, intra-tumoral heterogeneity within different disease compartments (e.g., skin, blood) further added complexity to SS, possibly creating obstacles for the diagnosis of the disease [ 11 ], which remains unexplored. Therefore, the identification of a body of diagnostic malignant cell markers, especially from different compartments, and their optimal combination have great potential in improving the diagnostic rate of SS and its early diagnosis.…”

Efeito de nanovesículas extracelulares derivadas de linhagens tumorais de linfoma T cutâneo em queratinócitos imortalizados

“…transportam em maior abundância a integrina da família β1 (ITGB1). Recentemente, ITGB1 foi proposto como possível alvo terapêutico na SS, pelo fato de ser um achado comum entre diferentes estudos de análises de expressão gênica em pacientes com SS (Cristofoletti et al 2022). A imensa heterogeneidade entre as células tumorais de pacientes SS (Borcherding et al 2022, Rassek and Iżykowska 2020) tem sido um desafio no melhor entendimento da patogênese da doença.…”