TOPIC: Melanoma and Other Skin Cancers 
Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in Cutaneous T-cell lymphoma  
Edda Blümel1, Andreas Willerslev-Olsen1, Maria Gluud1, Terkild Brink Buus1*, and Niels Ødum1*
1LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
*co-corresponding authors
Cutaneous T-cell lymphoma (CTCL) represents a group of non-Hodgkin lymphomas characterized by the accumulation of malignant CD4+ T cells in the skin. CTCL patients have an increased risk of contracting infections compared to healthy controls, which constitute a major cause of death. The most frequently found pathogen is Staphylococcus aureus, and reduction of colonizing bacteria in CTCL patients has been associated with clinical improvement and a decrease in tumour burden. However, while this suggests a link between bacterial infection and CTCL, the underlying mechanisms for their interaction are unclear. In this study, we aimed to investigate the role of the Staphylococcal alpha-toxin in CTCL. 
We used patient derived cell lines and primary cells from leukemic CTCL patients to study the effect of purified alpha-toxin in vitro. 
We demonstrate that malignant T cell lines as well as primary malignant CD4+ T cells from CTCL patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of CTCL patients, the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in non-malignant CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of the alpha-toxin receptor ADAM10 as well as other resistance mechanisms. 
In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant cells, identifying alpha-toxin as a putative drug target in CTCL.