Staphylococcus aureus induce drug resistance in cancer T cells in Sézary Syndrome

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  • Andreas Willerslev-Olsen
  • Lang Yan
  • Maria Danielsen
  • Emil Marek Heymans Pallesen
  • Karolina Wojewoda
  • Amra Osmancevic
  • Signe Hedebo
  • Yun-Tsan Chang
  • Lise M Lindahl
  • Sergei B Koralov
  • Larisa J Geskin
  • Susan E Bates
  • Lars Iversen
  • Rikke Bech
  • Marion Wobser
  • Emmanuella Guenova
  • Maria R Kamstrup

Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T cell lymphoma (CTCL), are prone to Staphylococcus aureus (S. aureus) infections and have a poor prognosis due to treatment-resistance. Here, we report that S. aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T-cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S. aureus and recombinant SE significantly inhibit cell death induced by HDAC inhibitor romidepsin in primary malignant T-cells from SS patients. Bacterial killing by engineered, bacteriophage-derived, S. aureus-specific endolysin (XZ.700) abrogates the effect of S. aureus supernatant. Likewise, mutations in MHC Class II binding sites of SE type-A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates TCR, NFB, and JAK/STAT signaling pathways (previously associated with drug-resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein Kinase C (upstream of NFB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by proteasome/NFB inhibitor bortezomib. Inhibition of JAK/STAT only blocks SE-induced rescue of malignant T-cells in some but not all patients, suggesting two distinct ways SE can induce drug resistance. In conclusion, we show that S. aureus enterotoxins induce drug-resistance in primary malignant T-cells. These findings suggest that S. aureus enterotoxins cause clinical treatment-resistance in SS patients and that anti-bacterial measures may improve the outcome of cancer-directed therapy in patients harboring S. aureus.

Original languageEnglish
Issue number15
Pages (from-to)1496–1512
Publication statusPublished - 2024

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