Figure 4 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
![(A) Malignant T-cells often express a monoclonal TCR-V-beta chain with decreased function of the whole TCR complex. Hence, SEs do not stimulate the TCR directly but through activation of benign T-cells. (B) SEs bind to MHC II expressed on malignant T-cells, which crosslink to TCR of benign T-cells. Subsequently, establishing T-T-cell interaction and IL-2 is expressed. (C) These signals induce IL-10 expression, which dampens the immune response via impaired maturation of DCs, repressed expression of Th1 cytokines (interferon-g, IL-12), inhibition of T-cell activation and promoted development of M2 macrophages. Reprinted with permission from ref. [105]. Copyright © 2014 American Society of Hematology.](publication/357949492/figure/fig3/AS:1122471541518338@1644629478395/A-Malignant-T-cells-often-express-a-monoclonal-TCR-V-beta-chain-with-decreased-function.png)
(A) Malignant T-cells often express a monoclonal TCR-V-beta chain with decreased function of the whole TCR complex. Hence, SEs do not stimulate the TCR directly but through activation of benign T-cells. (B) SEs bind to MHC II expressed on malignant T-cells, which crosslink to TCR of benign T-cells. Subsequently, establishing T-T-cell interaction and IL-2 is expressed. (C) These signals induce IL-10 expression, which dampens the immune response via impaired maturation of DCs, repressed expression of Th1 cytokines (interferon-g, IL-12), inhibition of T-cell activation and promoted development of M2 macrophages. Reprinted with permission from ref. [105]. Copyright © 2014 American Society of Hematology.
Source publication
Cutaneous T-Cell Lymphomas (CTCL) presents with substantial clinical variability and transcriptional heterogeneity. In the recent years, several studies paved the way to elucidate aetiology and pathogenesis of CTCL using sequencing methods. Several T-cell subtypes were suggested as the source of disease thereby explaining clinical and transcription...
Context in source publication
Context 1
... Vitro, SEs can stimulate CTCL disease activity via cell-cell contact of malignant and benign T-cells [105], which may act in a T-T-cell interaction manner by T-cells bearing MHC II [106,107] (Figure 4). Cross-linked TCR-MHC II prompts the benign T-cells to produce IL-2 which in turn upregulates the Janus kinase 3/signal transducer and activator of transcription 3 (Jak3/Stat3) pathway. ...
Similar publications
Background:
Treatment choices for patients with advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) who have failed first-line systemic therapies can be challenging, as several options are available. However, most evidence is based on observational and early phase studies due to the rarity of the disease. Mogamulizumab has recently been...
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of heavily pretreated mycosis fungoides/Sezary syndrome (MF/SS). Herein, we aimed to evaluate the outcomes of AHSCT for heavily pretreated patients with MF/SS retrospectively. This analysis included consecutive 19 patients with MF/SS who received 20 AHS...
The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a...
Aim: This study assessed the cost–utility of mogamulizumab, a novel monoclonal antibody, versus
established clinical management (ECM) in UK patients in previously treated advanced mycosis fungoides
(MF)/S ´ ezary syndrome (SS). Materials & methods: Lifetime partitioned survival model based on overall
survival, next treatment-free survival and the u...
The loss of CD47 on aging cells serves as a signal to macrophages to eliminate the target. Therefore, CD47 is a “do-not-eat-me” sign preventing macrophagal phagocytosis via interaction with its ligand SIRPα. Malignant lymphocytes of mycosis fungoides and Sézary syndrome express CD47 highly, thus, being ideal candidates for targeted anti-CD47 therap...
Citations
... External factors have been proposed as one of the key reasons for the aggravation of the disease (3)(4)(5). A recent hypothesis proposes that microbial antigens play a role in promoting chronic inflammation and malignant cell transformation (6); a similar role has been described in several other skin diseases, such as atopic dermatitis, psoriasis, and acne vulgaris (7)(8)(9)(10). Advances in modern technologies, and especially in the sequencing methods such as 16s sequencing and whole-genome shotgun sequencing (11), equip researchers with more tools they can use to understand changes in skin-microbial populations up to the species level in different CTCL disease stages and during therapeutic interventions. ...
... The balance of this heterogenous microbial community is essential for protecting the organism against invading pathogens and the breakdown of natural products (12). The microbiota can modulate the production of various anti-microbial peptides (AMPs), cytokines, and chemokines in the skin (5,9,12,13). Commensal skin microbiota, including bacteria such as Staphylococcus hominis (SH) or S. epidermidis (SE) (14), ubiquitously colonise human skin and are non-harmful to humans. ...
... The dysbiosis observed in the microbiome of CTCL patients is considered more than mere coincidence. Studies suggest that alterations in the microbiome can influence immune dysregulation, inflammation, and the progression of CTCL (4,9,15). Furthermore, microbial metabolites have been found to modulate T-cell responses and affect tumour microenvironments, potentially impacting disease outcomes (27,28). ...
Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders of skin-homing T cells causing chronic inflammation. These disorders cause impairment of the immune environment, which leads to severe infections and/or sepsis due to dysbiosis. In this study, we elucidated the host-microbial interaction in CTCL that occurs during the phototherapeutic treatment regime and determined whether modulation of the skin microbiota could beneficially affect the course of CTCL. EL4 T-cell lymphoma cells were intradermally grafted on the back of C57BL/6 mice. Animals were treated with conventional therapeutics such as psoralen + UVA (PUVA) or UVB in the presence or absence of topical antibiotic treatment (neomycin, bacitracin, and polymyxin B sulphate) as an adjuvant. Microbial colonisation of the skin was assessed to correlate with disease severity and tumour growth. Triple antibiotic treatment significantly delayed tumour occurrence (p = 0.026), which prolonged the survival of the mice (p = 0.033). Allocation to phototherapeutic agents PUVA, UVB, or none of these, along with antibiotic intervention, reduced the tumour growth significantly (p = 0.0327, p ≤ 0.0001, p ≤ 0.0001 respectively). The beta diversity indices calculated using the Bray−Curtis model showed that the microbial population significantly differed after antibiotic treatment (p = 0.001). Upon modulating the skin microbiome by antibiotic treatment, we saw an increase in commensal Clostridium species, e.g., Lachnospiraceae sp. (p = 0.0008), Ruminococcaceae sp. (p = 0.0001)., Blautia sp. (p = 0.007) and a significant reduction in facultative pathogens Corynebacterium sp. (p = 0.0009), Pelomonas sp. (p = 0.0306), Streptococcus sp. (p ≥ 0.0001), Pseudomonas sp. (p = 0.0358), and Cutibacterium sp. (p = 0.0237). Intriguingly, we observed a significant decrease in Staphylococcus aureus frequency (p = 0.0001) but an increase in the overall detection frequency of the Staphylococcus genus, indicating that antibiotic treatment helped regain the microbial balance and increased the number of non-pathogenic Staphylococcus populations. These study findings show that modulating microbiota by topical antibiotic treatment helps to restore microbial balance by diminishing the numbers of pathogenic microbes, which, in turn, reduces chronic inflammation, delays tumour growth, and increases survival rates in our CTCL model. These findings support the rationale to modulate the microbial milieu during the disease course of CTCL and indicate its therapeutic potential.
... [221][222][223] S. aureus is closely associated with cutaneous T-cell lymphoma and promotes the progression of this disease. 224 Staphylococcal-toxin (a-hemolysin) inhibits cytotoxic responses by T cells and lead to immune escape. 225 Staphylococcal enterotoxin produced by S. aureus can activate the STAT5 protein, causing an increase in Th2 cells. ...
Colonies formed by bacteria, archaea, fungi, and viral groups and their genomes, metabolites, and expressed proteins constitute complex human microbiomes. An increasing evidences showed that carcinogenesis and disease progression were link to microbiomes. Different organ sources, their microbial species, and their metabolites are different; the mechanisms of carcinogenic or procancerous are also different. Here, we summarize how microbiomes contribute to carcinogenesis and disease progression in cancers of the skin, mouth, esophagus, lung, gastrointestinal, genital, blood, and lymph malignancy. We also insight into the molecular mechanisms of triggering, promoting, or inhibiting carcinogenesis and disease progress induced by microbiomes or/and their secretions of bioactive metabolites. And then, the strategies of application of microorganisms in cancer treatment were discussed in detail. However, the mechanisms by which human microbiomes function are still poorly understood. The bidirectional interactions between microbiotas and endocrine systems need to be clarified. Probiotics and prebiotics are believed to benefit human health via a variety of mechanisms, in particular, in tumor inhibition. It is largely unknown how microbial agents cause cancer or how cancer progresses. We expect this review may open new perspectives on possible therapeutic approaches of patients with cancer.
... Interestingly, recent studies of the mouse model have shown that T-cell receptor engagement is an important factor of malignant transformation in CTCL (20). Moreover, progression of the disease also appeared to be dependent on microbiota (20,21). In addition, Staphylococcus aureus is known as the most common aetiological factor in infections in patients with CTCL, who are colonized by this bacteria in 44% up to 76% (22). ...
... In addition, Staphylococcus aureus is known as the most common aetiological factor in infections in patients with CTCL, who are colonized by this bacteria in 44% up to 76% (22). S. aureus superantigens may exacerbate and/or perpetuate the clonal expansion of the lymphoma concomitantly with spreading cutaneous inflammation (21,23). In addition, staphylococcal entero toxin A isolates have been shown to induce signal transducer and activator 3 (STAT3) activation and expression of IL-17, which pathway has been hypothesized as one of the oncogenic factors in CTCL (3,24). ...
... The constant responses of both malignant and benign lymphocytes to the S. aureus inflammation may contribute to carcinogenesis, which would explain why transient, aggressive antibiotic therapy may slow the tumour progression in some cases (22,27). S. aureus eradication may be a novel treatment for advanced MF/ SS in the future (21,28). ...
Tumour microenvironment has an important effect on the progression of cutaneous T-cell lymphomas. Using PCR with sequence-specific primers, this study analys- ed single-nucleotide polymorphisms in the interleu- kin-17 genes of 150 patients with cutaneous T-cell lymphoma. GG homozygote rs8193036 A/G of inter- leukin-17A gene occurred less commonly in the cuta- neous T-cell lymphoma group; however, patients with this single-nucleotide polymorphism experience sig- nificantly intense pruritus. Conversely, the rs2397084 AG heterozygote of interleukin-17F is more common in the lymphoma population. In addition, there were significant differences in the frequencies of interleu- kin-17 genotypes when comparing early (Ia to IIa) and advanced stages (IIb, III and IV) of this neoplasms. A similar result has been shown in comparison between Sézary syndrome and mycosis fungoides. The current data may serve as a possible explanation for the in- creased bacterial infection rates in the course of cuta- neous T-cell lymphoma, especially caused by Staphylo- coccus aureus. In summary, specific single-nucleotide polymorphisms occur with different frequencies bet- ween cutaneous T-cell lymphoma and healthy pa- tients. Moreover, genetic predisposition of seve- ral interleukin-17 single-nucleotide polymorphisms may be a factor causing impaired immune defence in cutaneous lymphomas.
... and lower relative abundance of Corynebacterium spp. in CTCL skin and high relative abundance of C. tuberculostearicum in stage IVA1 patients (100). Staphylococcus aureus was shown to contribute to CTCL progression (101). ...
Commensal bacteria and other microorganisms that reside in the human body are closely associated with the development and treatment of cancers. Recently, tumor microbiome (TM) has been identified in a variety of cancers such as pancreatic, lung, and breast cancers. TM has different compositions in different tumors and has different effects on tumors. TM plays an important role in the formation of the tumor microenvironment, regulation of local immunity, and modification of tumor cell biology, and directly affects the efficacy of drug treatment for tumors. TM is expected to be a biomarker for tumors, and engineered tumor-targeting bacteria and anti-cancer microbial agents (GEN-001) have an important role in the treatment of tumors. This paper reviews the relevant studies on TM in recent years and describes its distribution in different tumors, its correlation with clinical features, its effect on local immunity, and the research directions of TM in tumor treatment.
... Airborne toxins and potential carcinogenetic substances have been investigated as possible trigger of the disease with no clear correlation [10]. Infective agent susceptibility such as Staphylococcus aureus is thought to be involved in MF/SS pathogenesis and progression [11]. Genetic aberration along with cytokinc and inflammatory cell changes have been proposed as a putative candidate [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] sometimes providing contradictory results due to the small sample size or the use of different technique of investigation (immunohistochemistry and/or molecular biology analysis). ...
Mycosis fungoides (MF) and Sezary syndrome (SS) are the two most common type of cutaneous T-cell lymphoma (CTCL). Currently, no markers can be clearly related to prognosis or to differential diagnosis between early stages and inflammatory benign diseases (IBD). The thymocyte selection-associated high mobility group box factor (TOX), has been proposed as a possible marker in differential diagnosis between early CTCL stages and IBD. Recently TOX has been related to prognosis. We aimed to investigate whether TOX may be a diagnostic or prognostic marker. MF and SS biopsies between 2010 and 2020 were retrieved. New tissues slides were stained with an anti-TOX antibody, (Clone NAN448B). On each slide, 5 fields were examined at high magnification (400×), to evaluate the percentage of marker-positivity in a quantitative way. Thirty-six patients (12 females and 24 males) and 48 biopsies were collected. Nine patients had multiple biopsies. TOX expression in MF/SS cases showed an increase from early to advanced phases. TOX was not regarded as a prognostic marker due to the absence of significant changes by comparing early MF cases with reactive conditions. TOX statistical significance increased in patients alive with disease and in those dead of disease (p = 0.013 and = 0.0005, respectively) as compared with patients in complete remission. Our results show that TOX should be regarded more as a prognostic than a diagnostic marker.
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.
Dear Editor, Analysis of the skin microbiome has deepened our understanding of the deleterious role of microbial dysbiosis in skin conditions such as atopic dermatitis. Studies have implicated dysbiosis in promoting lymphoma-associated immune dysregulation. External antigens such as bacterial enterotoxins may trigger the innate immune system, leading to chronic inflammation and malignant transformation in cutaneous T-cell lymphoma (CTCL).¹
We aimed to determine the number of patients receiving microbial investigations (skin swabs/scrapings) in the CTCL clinic at one tertiary centre; the number of positive microbial investigations; and how many patients received timely and appropriate treatment(s).
In a retrospective cross-sectional study, the records of all patients attending the CTCL clinic from May to August 2022 were reviewed, to determine whether a swab had been taken, the result of the swab(s) and if appropriate antibiotics had been prescribed. Data were entered into an ad hoc table and analysed using descriptive statistics.
One hundred and seventy-five patients attended 22 clinics in total. Thirteen (7.4%) patients had microbial investigations performed (5.7% bacterial, 4.0% mycological, 2.3% both; Table 1). Of these, 70% (n = 7/10) of bacterial swabs were reported as positive and 29% (n = 2/7) of mycological investigations were positive.
Purpose of Review
Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME).
Recent Findings
There is increasing evidence challenging the model of TCM:mycosis fungoides (MF) and TEM:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway.
Summary
Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.
Skin microbiota have been linked to disease activity in cutaneous T-cell lymphoma (CTCL). As the skin microbiome has been shown to change after exposure to narrowband ultraviolet B (nbUVB) phototherapy, a common treatment modality used for CTCL, we performed a longitudinal analysis of the skin microbiome in CTCL patients treated with nbUVB. 16S V4 rRNA gene amplicon sequencing for genus-level taxonomic resolution, tuf2 amplicon next generation sequencing for staphylococcal speciation, and bioinformatics were performed on DNA extracted from skin swabs taken from lesional and non-lesional skin of 25 CTCL patients receiving nbUVB and 15 CTCL patients not receiving nbUVB from the same geographical region. Disease responsiveness to nbUVB was determined using the modified Severity Weighted Assessment Tool: 14 (56%) patients responded to nbUVB while 11 (44%) patients had progressive disease. Microbial α-diversity increased in nbUVB-responders after phototherapy. The relative abundance of Staphylococcus, Corynebacterium, Acinetobacter, Streptococcus, and Anaerococcus differentiated nbUVB responders and non-responders after treatment (q<0.05). Microbial signatures of nbUVB-treated patients demonstrated significant post-exposure depletion of S. aureus (q=0.024) and S. lugdunensis (q=0.004) relative abundances. Before nbUVB, responder lesional skin harboured higher levels of S. capitis (q=0.028) and S. warneri (q=0.026) than non-responder lesional skin. S. capitis relative abundance increased in the lesional skin of responders (q=0.05) after phototherapy; a similar upward trend was observed in non-responders (q=0.09). Post-treatment skin of responders exhibited significantly reduced S. aureus (q=0.008) and significantly increased S. hominis (q=0.006), S. pettenkoferi (q=0.021), and S. warneri (q=0.029) relative abundances compared to that of no-nbUVB patients. Staphylococcus species abundance was more similar between non-responders and no-nbUVB patients than between responders and no-nbUVB patients. In sum, the skin microbiome of CTCL patients who respond to nbUVB is different from that of non-responders and untreated patients, and is characterized by shifts in S. aureus and S. lugdunensis. Non-responsiveness to phototherapy may reflect more aggressive disease at baseline.
