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Review
. 2022 Jun 9;14(12):2847.
doi: 10.3390/cancers14122847.

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

Cristina Cristofoletti  1 , Antonella Bresin  1 , Martina Fioretti  1 , Giandomenico Russo  1 , Maria Grazia Narducci  1
Affiliations
Review

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

Cristina Cristofoletti et al. Cancers (Basel). .

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.

Keywords: Sézary syndrome; biochemical signals; blood and skin microenvironment; cutaneous T-cell lymphoma; heterogeneity; immunophenotype; single cell analysis; transcriptome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular signals emerging from comparison between paired skin- and blood-derived SS cells. Comparison analyses performed between paired skin- and blood-derived SS cells highlight the molecular signals triggered in these two SS cell subpopulations.
Figure 2
Figure 2
Intratumor heterogeneity of Sézary cells. Skin- and blood-derived SS cells showed differences in proliferation capacity, expression of activation markers, and level of transcriptional heterogeneity. Blood SS cells showed phenotypic heterogeneity, which also was evaluated under specific culture conditions and in the PDX mouse model.
Figure 3
Figure 3
Shared and unique deregulated genes between malignant and normal CD4+ cells in three high-throughput studies.
See this image and copyright information in PMC

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