The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways.

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21WAF1/Cip1, and p27Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.

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

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.

New Genetic Markers of Skin T-Cell Lymphoma Treatment.

AIM: Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. MATERIALS AND METHODS: A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. RESULTS: The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. CONCLUSION: Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

GATA-3-dependent Gene Transcription is Impaired upon HDAC Inhibition.

PURPOSE: Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas. EXPERIMENTAL DESIGN: Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi. RESULTS: We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL. CONCLUSIONS: Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3-driven lymphoproliferative neoplasms.

What's New in Cutaneous T-Cell Lymphoma-Associated Pruritus.

Cutaneous T-cell lymphomas are a heterogenous group of lymphomas that cause various skin manifestations. Severe pruritus occurs frequently in cutaneous T-cell lymphoma and negatively impacts patients' quality of life. The pathophysiology of cutaneous T-cell lymphoma-associated itch is complex and involves various immune cells, inflammatory cytokines, and neuroimmune interactions. Treating cutaneous T-cell lymphoma pruritus can be challenging, and there have been few randomized controlled studies evaluating the use of antipruritic treatments in these patients. Systemic therapies targeting the disease have also been shown to have some antipruritic effects. Furthermore, although biologic therapy has revolutionized the treatment of other pruritic skin conditions, the use of biologics in cutaneous T-cell lymphoma remains controversial.

A Case Series on the Use of Brentuximab Vedotin for the Treatment of Mycosis Fungoides.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody that appears to be more effective against CD30-expressing cutaneous T-cell lymphoma (CTCL) compared to current standard-of-care treatments.   Objective: To determine the real-world efficacy and adverse effects of BV use in patients with mycosis fungoides (MF) who were treated with BV at Atrium Health Wake Forest Baptist Medical Center. METHODS: Study staff performed a retrospective chart review of patients diagnosed with MF who were prescribed BV at Atrium Health Wake Forest Baptist Comprehensive Cancer Center. RESULTS:   Regardless of their response to BV, all patients in our cohort had higher CD30 positivity on subsequent biopsies compared to their initial skin biopsy.  Conclusions: Improved understanding of appropriate CD30 testing and evaluation will allow for quicker invention of patients with BV responsive CTCL.  J Drugs Dermatol. 2023;22(12):e33-e34.    doi:10.36849/JDD.6981e.

Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection.

Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.

In vitro evaluation of Neosetophomone B inducing apoptosis in cutaneous T cell lymphoma by targeting the FOXM1 signaling pathway.

BACKGROUND: Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. OBJECTIVE: In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. METHODS: Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. RESULTS: NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. CONCLUSION: Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.

Embelin inhibits viability of cutaneous T cell lymphoma cell lines HuT78 and H9 by targeting inhibitors of apoptosis.

Cutaneous T cell lymphoma (CTCL) is a varied group of neoplasms that affects the skin. Acquired resistance against chemotherapeutic drugs and associated toxic side effects are limitations that warrant search for novel drugs against CTCL. Embelin (EMB) is a naturally occurring benzoquinone derivative that has gained attention owing to its anticancer pharmacological actions and nontoxic nature. We assessed the anticancer activity of EMB against CTCL cell lines, HuT78, and H9. EMB inhibited viability of CTCL cells in a dose-dependent manner. EMB activated extrinsic and intrinsic pathways of apoptosis as shown by the activation of initiator and executioner caspases. EMB-induced apoptosis also involved suppression of inhibitors of apoptosis, XIAP, cIAP1, and cIAP2. PARP cleavage and upregulation of pH2AX indicated DNA damage induced by EMB. In conclusion, we characterized a novel apoptosis-inducing activity of EMB against CTCL cells, implicating EMB as a potential therapeutic agent against CTCL.

Overall survival in the UK in mycosis fungoides or Sézary syndrome cutaneous T-cell lymphoma: comparative effectiveness of mogamulizumab versus current standard of care.

Aim: Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with patients with previously treated advanced mycosis fungoides/Sézary syndrome (MF/SS) in real-world setting. Design, setting & participants: Data were from the Hospital Episode Statistics database (all patients in NHS secondary care system in 2009-2019). Patients were selected according to trial inclusion criteria, then trial and HES samples were matched on selected variables with significant imbalance. Outcomes: The analysis indicated significant improvement in OS for mogamulizumab treatment compared with UK clinical practice (hazard ratio: 0.36, 95% CI: 0.24, 0.53). Conclusion: Results suggest an OS advantage for patients with advanced MF/SS treated with mogamulizumab in MAVORIC trial compared with UK clinical practice.

An update on mechanisms of pruritus and their potential treatment in primary cutaneous T-cell lymphoma.

Primary cutaneous T-cell lymphomas (CTCL), which include mycosis fungoides (MF) and Sézary syndrome (SS), are a group of lymphoproliferative disorders characterized by clonal accumulation of neoplastic T-lymphocytes in the skin. Severe pruritus, one of the most common and distressing symptoms in primary CTCL, can significantly impair emotional well-being, physical functioning, and interpersonal relationships, thus greatly reducing quality of life. Unfortunately, effectively managing pruritus remains challenging in CTCL patients as the underlying mechanisms are, as of yet, not fully understood. Previous studies investigating the mechanisms of itch in CTCL have identified several mediators and their corresponding antagonists used for treatment. However, a comprehensive overview of the mediators and receptors contributing to pruritus in primary CTCL is lacking in the current literature. Here, we summarize and review the mediators and receptors that may contribute to pruritus in primary CTCL to explore the mechanisms of CTCL pruritus and identify effective therapeutic targets using the PubMed and Web of Science databases. Studies were included if they described itch mediators and receptors in MF and SS. Overall, the available data suggest that proteases (mainly tryptase), and neuropeptides (particularly Substance P) may be of greatest interest. At the receptor level, cytokine receptors, MRGPRs, and TRP channels are most likely important. Future drug development efforts should concentrate on targeting these mediators and receptors for the treatment of CTCL pruritus.

Reprogramming of PD-1+ M2-like tumor-associated macrophages with anti-PD-L1 and lenalidomide in cutaneous T cell lymphoma.

Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti-programmed cell death ligand 1 (anti-PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti-PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti-PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti-PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.