Abstract
Sézary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS.
Highlights
IntroductionIn IHC experiments, Ki67+ Sézary syndrome (SS) cells were calculated by a pathologist, counting at least 400 tumor cells in high-power fields with a 40x object lens; c A positive correlation between matched skin-PI values and tumor burden expressed as expansion of circulating clonal TCR-Vβ+ cells was observed (n = 17, R = 0.73, P = 0.001 for Spearman test) mainly activated in skin tumor cells with respect to blood [20]
Sézary syndrome (SS) is a rare aggressive leukemic variant of cutaneous T-cell lymphomas (CTCLs) in which malignantElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.T cells accumulate in the skin, lymph nodes and blood, typically resulting in a shortened life expectancy with a median of survival of 63 months [1, 2].SS cells express CD45R0 + CCR7 + CD27 + CD62L+ with a central memory (CM) T cells phenotype representing mature long-lived lymphocytes with a high proliferative and migratory potential [3]
The percentage of Ki67 + SS cells was calculated, using a gating strategy, within the neoplastic clone recognized by the co-expression of CD3, CD4, CCR7 and the specific rearrangement of TCR-Vβ chain by FACS as showed in Figure S1 and by double IHC
Summary
In IHC experiments, Ki67+ SS cells were calculated by a pathologist, counting at least 400 tumor cells in high-power fields with a 40x object lens; c A positive correlation between matched skin-PI values and tumor burden expressed as expansion of circulating clonal TCR-Vβ+ cells was observed (n = 17, R = 0.73, P = 0.001 for Spearman test) mainly activated in skin tumor cells with respect to blood [20]. These data underline how different environments, as skin and blood, may affect SS cells in response to stimulatory or co-stimulatory signals [20]
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