“Alterations in the Skin Microbiota Are Associated With Symptom Severity in Mycosis Fungoides”

Zhang, Yumeng; Seminario‐Vidal, Lucia; Cohen, Leah; Hussaini, Mohammad; Yao, Jiqiang; Rutenberg, David; Kim, Young‐Chul; Giualiano, Anna; Robinson, Lary A.; Sokol, Lubomir

doi:10.3389/fcimb.2022.850509

Cited by 15 publications

(11 citation statements)

References 35 publications

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“…Therefore, we hypothesized that MF patients have a more signi cant disturbance of the skin microbiome beyond the mere presence of pathogenic microbes like S. aureus. So far, several reports characterized the MF skin microbiome [23][24][25][26][27] and indicated that (a) a destabilized microbiome and [23,28] (b) the abundance of certain microbial genera like Cutibacteria or Staphylococci [24,25] might be associated with disease severity. However, statistical signi cance was largely not reached, likely because of small sample sizes [24], characterization approaches that lacked resolution at the microbial species level, or because samples were not categorized based on clinical or lesional stages [28].…”

Section: Introductionmentioning

confidence: 99%

The Skin Microbiome Stratifies Patients with Cutaneous T Cell Lymphoma and Determines Event-Free Survival

Licht¹,

Dominelli²,

Kleemann

et al. 2023

Preprint

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Background: Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas that are characterized by the presence of clonal malignant T cells in the skin, with Mycosis fungoides (MF) being the most common entity. The role of the skin microbiome for MF development and progression are currently poorly understood. Methods: We used shotgun metagenomic profiling, real-time qPCR and T cell receptor sequencing to compare lesional and nonlesional skin of 20 patients with early and advanced MF that were treated at two independent German skin cancer centres. Additionally, Staphylococcus aureus and other bacterial species were isolated from MF skin for functional profiling and to investigate the S. aureus virulence factor spa. Results: We identified a subgroup of MF patients that exhibited a substantial dysbiosis on MF lesions with concomitant outgrowth of S. aureuson plaque while the other MF patients presented with a balanced microbiome on lesional skin. Dysbiosis and S. aureus outgrowth were accompanied with ectopic levels of cutaneous antimicrobial peptides (AMPs) and increased adaptation of the outgrowing, plaque-derived S. aureus strains, which may have resulted in or contributed to these microbiome perturbations. Furthermore, the plaque-derived S. aureus strains showed a reduced susceptibility towards antibiotics and an upregulation of the virulence factor spa, which also exhibited a potential gain-of-function mutation, that may render it highly potent to activate the NF-κB pathway. Last, we observed a restricted T cell receptor repertoire and a reduced event-free survival in patients with dysbiosis on MF lesions. Conclusions: Our data suggest that virulent, outgrowing S. aureus strains fuel pathogenesis in the MF patient subgroup with dysbiosis, possibly via highly potent spa that activates the NF-κB pathway. We therefore provide a solid basis for the role of the skin microbiome for MF progression and pave the way for potential microbiome modulating treatments specifically targeting S. aureus to prevent MF disease progression.

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Section: Introductionmentioning

confidence: 99%

The Skin Microbiome Stratifies Patients with Cutaneous T Cell Lymphoma and Determines Event-Free Survival

Licht¹,

Dominelli²,

Kleemann

et al. 2023

Preprint

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“…This work further contributes to a growing body of knowledge that suggests CTCL is a disease associated with global dysbiosis ( 10 – 16 ). The data herein support our previous findings on the CTCL gut microbiome, namely that patients with more advanced disease demonstrated decreased phylogenic diversity and loss of beneficial commensal taxa in comparison to healthy controls ( 11 ).…”

Section: Discussionmentioning

confidence: 63%

“…Broad-spectrum antibiotic treatment correlates with reduced tumor burden in some patients, and spontaneous CTCL mouse models exhibit mild, indolent disease when housed in germ-free isolators but have rapid disease progression when moved to traditional housing ( 8 , 9 ). Recent work published by our group and others has demonstrated that CTCL patients are globally dysbiotic, with altered skin, gut, and nasal microbiomes ( 10 – 16 ) and that dysbiosis worsens with disease severity ( 10 – 12 , 16 , 17 ).…”

Section: Introductionmentioning

confidence: 97%

Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment

Nguyen,

Chrisman,

Enriquez

et al. 2024

Front. Immunol.

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Recent studies have shown a close relationship between cutaneous T-cell lymphoma (CTCL) and its microbiome. CTCL disease progression is associated with gut dysbiosis and alterations in bacterial taxa parallel those observed in immunologically similar atopic dermatitis. Moreover, the microbial profile of lesional skin may predict response to narrowband ultraviolet B (nbUVB), a common skin-directed therapy. However, the relationship between the gut microbiome, an immunologically vital niche, and nbUVB remains unexplored in CTCL. Herein, we performed 16S rRNA sequencing and PICRUSt2 predictive metagenomics on DNA extracted from stool swabs of 13 CTCL patients treated with nbUVB, 8 non-treated patients, and 13 healthy controls. Disease response was assessed with modified Severity Weighted Assessment Tool (mSWAT); of nbUVB-treated patients, 6 improved (decreased mSWAT), 2 remained stable, and 5 worsened (increased mSWAT). Protective commensal bacteria including Lactobacillaceae and Erysipelatoclostridiaceae were significantly less abundant in CTCL patients compared to controls. With treatment, the CTCL gut microbiome exhibited decreased phylogenetic diversity and lower relative abundance of pro-inflammatory Sutterellaceae. Sutterellaceae was also significantly more abundant in patients who worsened, and Eggerthellaceae and Erysipelotrichaceae trended higher in patients who improved. Finally, PICRUSt2 functional predictions based on shifts in abundance of bacterial sequences repeatedly identified alterations in inositol degradation, which plays a key role in host immunomodulation, including inositol phospholipid signaling relevant to T-cell survival and proliferation. Our results bolster the paradigm of gut dysbiosis in CTCL and its functional implications in disease pathogenesis, and further delineate bacterial taxa associated with nbUVB response and with nbUVB treatment itself.

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“…CTCL is characterized by heightened vulnerability to bacterial infections, contributing significantly to disease-related morbidity and mortality. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 Skin barrier defects induced by malignant T cells are likely ports of entrance for bacterial infection. 28 , 29 , 30 …”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome

Vadivel,

Willerslev-Olsen,

Namini

et al. 2024

Blood

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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.

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“Alterations in the Skin Microbiota Are Associated With Symptom Severity in Mycosis Fungoides”

Cited by 15 publications

References 35 publications

The Skin Microbiome Stratifies Patients with Cutaneous T Cell Lymphoma and Determines Event-Free Survival

The Skin Microbiome Stratifies Patients with Cutaneous T Cell Lymphoma and Determines Event-Free Survival

Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment

Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome

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