Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome

Abstract

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.

Modulation of the skin microbiome in cutaneous T-cell lymphoma delays tumour growth and increases survival in the murine EL4 model

“…We have explored the impact of the skin microbiome modulation, through antibiotics and phototherapy, on disease progression in CTCL. In light of the groundbreaking findings by Vadivel et al (36), demonstrating that S. aureus can induce drug resistance in malignant T cells, our study gains additional significance. This resistance is mediated through pathways previously implicated in CTCL pathogenesis and treatment resistance, notably TCR, NFkB, and JAK/STAT signaling.…”

“…Therefore, our data suggest that combining phototherapy with targeted antimicrobial strategies could offer a twofold benefit: direct tumor cell cytotoxicity and disruption of bacterial-mediated resistance mechanisms. This approach, opens new avenues for enhancing the efficacy of existing and future therapeutic strategies against CTCL, warranting further investigation (36).…”

Vitamin D in Cutaneous T-Cell Lymphoma

“…Importantly, the risk of skin colonization by S. aureus increases with disease progression, and between one-third and two-thirds of patients with advanced disease harbor S. aureus , a large proportion of which produce toxins such as staphylococcal enterotoxins (SEs) [ 121 , 125 ]. This colonization not only poses a risk for invasive infections but also appears to exacerbate disease activity and potentially contributes to drug resistance in malignant T cells [ 120 , 127 , 128 ].…”

Therapeutic Opportunities in Cutaneous T-cell Lymphoma

“…Staphylococcal enterotoxins (SE) protect malignant T cells from HDACi, while chemotherapeutic drugs and metabolic inhibitors induce cell death. Interestingly, JAK/STAT signalling is one of the driving pathways of this process, and its inhibition through Tofacitinib can block the SE-induced Romidepsin (HDACi) resistance [20]. Thus, JAK inhibitors could be potentially used to overcome the S. aureusinduced drug resistance.…”