The phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL), which includes the mycosis fungoides and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL. We compared the efficacy of three rapalogs (rapamycin, temsirolimus, and everolimus) and the dual-mTOR/PI3K inhibitor PF-04691502 (hereinafter PF-502) in four CTCL cell lines. PF-502 was revealed to be the most effective inhibitor of cell growth. Interestingly, PF-502 also exerted its antitumor activity in patient-derived CTCL cells and in a xenograft mouse model, where it induced significant apoptosis and increased survival of treated mice. Furthermore, we found an inverse correlation between PTEN gene expression and the ability of PF-502 to induce apoptosis in SS cells. Our data strongly support the therapeutic potential of dual PI3K/mTOR inhibitors in CTCL.

Sezary syndrome (SS) is a primary cutaneous T-cell lymphoma (CTCL) characterized by erythroderma, lymphadenopathy and leukemic involvement of the peripheral blood. The high relapse rates and a poor prognosis complicate its clinical course and treatment. The phenotypic characterization and genomic/transcriptomic approaches revealed high heterogeneity of Sezary cells, identifying a wide spectrum of biomarkers implicated in the development of this lymphoma. In this context, we discuss the major malignancy-related biomarkers reported in the literature for the diagnosis, prognosis and staging of SS. The hope for a single reliable diagnostic marker appears increasingly unrealistic, but the discovery of multiple potential biomarkers, with pathogenetic implications, paves the road to promising personalized therapies in SS.

(1) Background: Vitiligo is an autoimmune skin disorder characterized by melanocyte destruction. Despite metabolic disturbances and oxidative stress also playing a key role in its pathogenesis, accumulating evidence highlights a prominent role for cytokine dysregulation. (2) Methods: A systematic search was conducted to identify meta-analyses published in the last decade that investigated cytokine involvement in vitiligo. (3) Results: Based on predefined inclusion criteria, nine meta-analyses were retrieved and reviewed. The findings confirm a central role for interferon-gamma (IFN-γ) in vitiligo pathogenesis, although recent meta-analyses suggest that IFN-γ gene polymorphisms are more broadly associated with autoimmunity rather than being vitiligo-specific. Elevated interleukin-17 (IL-17) levels have been consistently reported in vitiligo patients, supporting its contribution to immune-mediated melanocyte destruction. Regulatory T cell dysfunction appears to play a crucial role in disease progression. Additionally, TNF-α-308 G/A polymorphism has been linked to a genetic susceptibility to vitiligo, particularly in specific populations, reinforcing the role of TNF-α in immune dysregulation. Lastly, chemokines involved in immune cell recruitment to melanocytes further illustrate the complex inflammatory network underlying the disease. (4) Conclusions: This systematic review consolidates evidence from a decade of meta-analyses, underscoring the significance of cytokine dysregulation in vitiligo and highlighting potential therapeutic targets.

Sézary syndrome (SS) is a rare and aggressive variant of cutaneous T-cell lymphoma. It is characterized by the copresence of CD4+ neoplastic lymphocytes, named Sezary cells, mainly in the blood, lymph nodes, and skin where they induce chronic inflammation that in turn impairs the patient's QOL and fuels neoplastic cells. SS is not readily cured, but immunotherapy is becoming an effective option for this lymphoma. In this study, we investigated, in a large cohort of patients with SS, the expression and function of the immune checkpoint molecule CD39, which degrades proinflammatory extracellular adenosine triphosphate. We showed that the SNP rs10748643 A/G within the ENTPD1 gene coding for the CD39 protein controls its expression level. Patients carrying the A/G‒G/G genotype showed a significantly higher frequency of clonal CD4+CD39+ SS cells than those carrying the A/A genotype. Different from other cancers, high CD39 expression correlates with a better prognosis. Comparing primary G/G with A/A lymphoma cells, we observed that G/G SS cells have a higher ability to degrade adenosine triphosphate, increased apoptotic susceptibility, and upon activation, reduced IL-2 production. Accordingly, CD39 enzymatic inhibition enhances SS cell viability and IL-2 production on activation. These results strongly suggest a special caution for SS treatment with therapeutic inhibitors of CD39.

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.