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Cutaneous T-cell lymphoma (CTCL) is characterized by malignant T-cells proliferating in a unique tumor microenvironment (TME) dominated by keratinocytes. Skin colonization and infection by Staphylococcus aureus(S. aureus) is a common cause of morbidity and suspected of fueling disease activity. Here we show that expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes correlates with IFN-γ expression in the TME. Importantly, IFN-γ induces HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. Likewise, preincubation of keratinocytes with supernatant from patient-derived SE-producing S. aureustriggers proliferation in malignant T-cells and cytokine release (including IL-2), when cultured with non-malignant T-cells. This is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. Furthermore, mutations in the HLA-DR binding sites of SE type-A, and siRNA-mediated knockdown of Janus Kinase-3 (JAK3) and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that, upon exposure to patient-derived S. aureusand SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureusmediated disease activity in CTCL.

•Enterotoxins from S aureusbacteria induce drug resistance in primary malignant T cells in SS.•Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance.

Staphylococcus aureusis suspected to fuel disease activity in cutaneous T-cell lymphomas. In this study, we investigate the effect of a recombinant, antibacterial protein, endolysin (XZ.700), on S. aureusskin colonization and malignant T-cell activation. We show that endolysin strongly inhibits the proliferation of S. aureusisolated from cutaneous T-cell lymphoma skin and significantly decreases S. aureusbacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureusis profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureusinduction of IFNγand the IFNγ-inducible chemokine CXCL10in healthy skin. Whereas patient-derived S. aureusstimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving nonmalignant T cells, endolysin strongly inhibits the effects of S. aureuson activation (reduced CD25 and signal transducer and activator of transcription 5 phosphorylation) and proliferation (reduced Ki-67) of malignant T cells and cell lines in the presence of nonmalignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureusand blocks their potential tumor-promoting effects on malignant T cells.