ABSTRACT: It is unknown why cutaneous T cell lymphoma (CTCL) progress from a relative indolent skin condition to severe cancer with a poor prognosis. Staphylococcus aureus (SA) has been suspected to play a role, because antibiotics have an inhibitory effect on the tumor burden in some patients. As these patients often display skin colonization by SA, it was hypothesized, but never proven, that SA generate a pro-oncogenic milieu in lesional skin. Here, we study the effect of short-term aggressive antibiotic treatment on tumor cells, the microenvironment, and disease activity in treatment-refractory, advanced stage CTCL. We report that advanced stage CTCL patients experienced significant decrease in clinical and patient-self-reported symptoms in response to aggressive 4-week antibiotic therapy, which eradicated SA. Notably, the clinical improvement lasted for more than 8 months in some patients. Global mRNA expression and cell-signaling pathway analysis indicated a decrease in IL-2 signaling, inflammation, and mitosis in skin lesions after antibiotic therapy. In accordance, IL-2 receptor chain (IL2R-) expression, STAT3 activation, and mitotic activity were decreased in lesional skin following antibiotic treatment. Conversely, SA toxins triggered IL2R- expression, STAT3 activation, and enhanced proliferation ex vivo in primary malignant T cells derived from untreated patients. In conclusion, we demonstrate that transient, aggressive antibiotic treatment inhibits tumor cells, partly normalizes the microenvironment, and decreases disease activity in lesional skin. Thus, we provide a first mechanistic link between antibiotics, skin inflammation, and tumor burden and therefore a novel rationale for treatment of SA in advanced CTCL.
