Old Sins Cast Long Shadows: News on Staphylococcus aureus in Cutaneous T Cell Lymphoma

View Large Image Figure ViewerDownload Hi-res image Download (PPT) Patients with cutaneous T-cell lymphoma (CTCL) face an increased susceptibility to bacterial infections, and among these infections, Staphylococcus aureus (S aureus) stands out as a major causative pathogen (Bobrowicz et al., 2020Bobrowicz M Fassnacht C Ignatova D Chang YT Dimitriou F Guenova E Pathogenesis and therapy of primary cutaneous T-Cell lymphoma: collegium internationale allergologicum (CIA) update 2020.Int Arch Allergy Immunol. 2020; 181: 733-745Google Scholar). In fact, over half of the patients afflicted with advanced-stage CTCL succumb to infections rather than the cancer itself, emphasizing the crucial clinical significance of bacterial complications, especially in those with advanced disease (as reviewed in the study by Willerslev-Olsen et al., 2013Willerslev-Olsen A. Krejsgaard T. Lindahl L.M. Bonefeld C.M. Wasik M.A. Koralov S.B. et al.Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.Toxins. 2013; 5: 1402-1421Google Scholar). Moreover, for decades, there has been a suspicion that S aureus plays a direct role in the pathogenesis of CTCL, fueling disease activity (Willerslev-Olsen et al., 2013Willerslev-Olsen A. Krejsgaard T. Lindahl L.M. Bonefeld C.M. Wasik M.A. Koralov S.B. et al.Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.Toxins. 2013; 5: 1402-1421Google Scholar). Skin colonization by toxin-producing S aureus has been consistently reported in CTCL (Jackow et al., 1997Jackow C.M. Cather J.C. Hearne V. Asano A.T. Musser J.M. Duvic M. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.Blood. 1997; 89: 32-40Google Scholar, as reviewed in Willerslev-Olsen et al., 2013Willerslev-Olsen A. Krejsgaard T. Lindahl L.M. Bonefeld C.M. Wasik M.A. Koralov S.B. et al.Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.Toxins. 2013; 5: 1402-1421Google Scholar). Staphylococcal toxins, including staphylococcal enterotoxins (SE) and staphylococcal alphatoxin, seem to play a significant role in the pathogenesis of CTCL, affecting various mechanisms, such as super-antigenic stimulation of malignant T cells and modulation of the tumor microenvironment to express malignant T-cell growth factors, proto-oncogenes, and oncomiRs (Tokura et al., 1992Tokura Y. Heald P.W. Yan S.L. Edelson R.L. Stimulation of cutaneous T-cell lymphoma cells with superantigenic staphylococcal toxins.J Invest Dermatol. 1992; 98: 33-37Google Scholar; Lindahl et al., 2019Lindahl L.M. Willerslev-Olsen A. Gjerdrum L.M.R. Nielsen P.R. Blümel E. Rittig A.H. et al.Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.Blood. 2019; 134: 1072-1083Google Scholar; Willerslev-Olsen et al., 2013Willerslev-Olsen A. Krejsgaard T. Lindahl L.M. Bonefeld C.M. Wasik M.A. Koralov S.B. et al.Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.Toxins. 2013; 5: 1402-1421Google Scholar). Those earlier studies primarily relied on conventional microbiological methodologies, such as bacterial culture and SE-protein detection. However, recent investigations using high-throughput sequencing to study the skin microbiome have yielded some conflicting results in the context of CTCL. For instance, one study found equal levels of S aureus colonization in both lesional and nonlesional skin, challenging the previously assumed clinical significance of S aureus in CTCL (Salava et al., 2020Salava A. Deptula P. Lyyski A. Laine P. Paulin L. Väkevä L. et al.Skin microbiome in cutaneous T-cell lymphoma by 16S and whole-genome shotgun sequencing.J Invest Dermatol. 2020; 140: 2304-2308.e7Google Scholar). In their recent publication in the Journal of Investigative Dermatology, Liu et al. present a compelling study in which they integrate high-throughput sequencing with classical microbiological techniques, encompassing a larger cohort of patients with CTCL (Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar). The investigators collected bacteriological samples from the lesional and contralateral nonlesional skin of 66 patients diagnosed with mycosis fungoides and Sézary syndrome, which are the most prevalent and severe variants of CTCL, respectively. Notably, one-third of the patients exhibited S aureus colonization on their lesional skin. Moreover, the frequency of lesional skin colonization by S aureus escalated with disease progression, rising from 12% in early-stage (IA–IIA) patients to over 50% in those with advanced-stage disease (IIB–IVB) (Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar). Notably, S aureus was found in cultures from both lesional and nonlesional skin in most S aureus–positive patients. However, through high-throughput sequencing, the investigators observed that patients who had S aureus cultured from lesional skin displayed a notably higher proportion of S aureus on lesional skin compared with contralateral, nonlesional skin (Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar). Furthermore, it was observed that over a third of the isolated S aureus strains produced SE, confirming Duvic and co-workers’ milestone 1997 study (Jackow et al., 1997Jackow C.M. Cather J.C. Hearne V. Asano A.T. Musser J.M. Duvic M. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.Blood. 1997; 89: 32-40Google Scholar) and adding further weight to the notion that patients, especially those with advanced disease, frequently harbour SE-producing S aureus strains (Jackow et al., 1997Jackow C.M. Cather J.C. Hearne V. Asano A.T. Musser J.M. Duvic M. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.Blood. 1997; 89: 32-40Google Scholar). These findings hold significant importance for several reasons: (i) First, they confirm the frequent occurrence of S aureus colonization on lesional skin and, importantly, establish its correlation with disease progression. (ii) Second, the study demonstrates that S aureus colonization of lesional skin is a global concern affecting diverse ethnic groups that have been examined thus far. (iii) Third, the research documents that in S aureus–positive patients, the proportion of Staphylococcus on lesional skin significantly surpasses that of nonlesional skin, suggesting that the quantity of S aureus is a critical factor, rather than simply the presence or absence of S aureus on nonlesional skin. These findings also raise following series of intriguing questions: why are patients with CTCLparticularly susceptible to skin colonization and infection by S aureus? What role does S aureus and SE play in disease progression? In addition, what new treatment options are available and relevant in light of these discoveries? The investigators offer potential explanations to these inquiries. According to their observations, since S aureus colonization is infrequent in early-stage disease, Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar conclude that S aureus may not be involved in disease initiation, as originally suggested (Tokura et al., 1992Tokura Y. Heald P.W. Yan S.L. Edelson R.L. Stimulation of cutaneous T-cell lymphoma cells with superantigenic staphylococcal toxins.J Invest Dermatol. 1992; 98: 33-37Google Scholar). Instead, it might serve as an exogenous factor fuelling an ongoing disease process, as proposed by Willerslev-Olsen et al., 2013Willerslev-Olsen A. Krejsgaard T. Lindahl L.M. Bonefeld C.M. Wasik M.A. Koralov S.B. et al.Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.Toxins. 2013; 5: 1402-1421Google Scholar In support of this notion, a study conducted on a cohort of 43 twins with CTCL revealed that bacterial infections were observed after diagnosis in all but one case. This finding emphasizes that the disease appears to precede an increased susceptibility to bacterial infections (Odum et al., 2017Odum N. Lindahl L.M. Wod M. Krejsgaard T. Skytthe A. Woetmann A. et al.Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins.Blood Cancer J. 2017; 7: e517Google Scholar). Importantly, none of the 43 cotwins developed CTCL during an observation period of up to 33 years, and none of them displayed a heightened susceptibility to bacterial infections when compared to the CTCL-positive case-twins and a matched background population (Odum et al., 2017Odum N. Lindahl L.M. Wod M. Krejsgaard T. Skytthe A. Woetmann A. et al.Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins.Blood Cancer J. 2017; 7: e517Google Scholar). Taken together, these findings indicate that CTCL is not an inherited disease and, more important in this context, the susceptibility to bacterial infections is not genetically determined in CTCL (Odum et al., 2017Odum N. Lindahl L.M. Wod M. Krejsgaard T. Skytthe A. Woetmann A. et al.Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins.Blood Cancer J. 2017; 7: e517Google Scholar). In contrast, the susceptibility to skin colonization by S aureus appears to be a consequence of the progressive disease process. A recent study demonstrated that malignant T cells drive changes in the tumor microenvironment, leading to a decrease in the expression of skin barrier proteins, such as filaggrin in lesional skin (Gluud et al., 2023Gluud M. Pallesen E.M.H. Buus T.B. Gjerdrum L.M.R. Lindahl L.M. Kamstrup M.R. et al.Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.Blood. 2023; 141: 180-193Google Scholar). Notably, both malignant and nonmalignant T cells produce cytokines that suppress filaggrin expression by nearby keratinocytes (Gluud et al., 2023Gluud M. Pallesen E.M.H. Buus T.B. Gjerdrum L.M.R. Lindahl L.M. Kamstrup M.R. et al.Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.Blood. 2023; 141: 180-193Google Scholar). In addition, the deficiency in the skin barrier progressively worsens with disease advancement (Gluud et al., 2023Gluud M. Pallesen E.M.H. Buus T.B. Gjerdrum L.M.R. Lindahl L.M. Kamstrup M.R. et al.Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.Blood. 2023; 141: 180-193Google Scholar). It is well-established in other inflammatory skin diseases, such as atopic dermatitis that filaggrin deficiency increases the risk of skin colonization by S aureus. Conversely, filaggrins and filaggrin degradation products have been found to exert anti-S aureus activity. Consequently, it is plausible that the deteriorating skin condition and the progressively compromised skin barrier with disease advancement contribute to the escalating risk of S aureus skin colonization, as reported by Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar. In contrast, nonlesional skin in patients with CTCL remains largely intact, which aligns with the observations made by Lui et al, that nonlesional skin may become colonized by S aureus in patients with CTCL, similar to that observed in healthy individuals. However, the bacterial loads are significantly lower, and there are no adverse consequences on the underlying skin, as it remains safeguarded by an intact skin barrier (Gluud et al., 2023Gluud M. Pallesen E.M.H. Buus T.B. Gjerdrum L.M.R. Lindahl L.M. Kamstrup M.R. et al.Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma.Blood. 2023; 141: 180-193Google Scholar; Liu et al., 2023Liu X. Sun J. Gao Y. Liu Fengjie Pan Haihao Tu P. et al.Characteristics of Staphylococcus aureus colonization in cutaneous T cell lymphoma.J Invest Dermatol. 2023; (S0022-202X:02427–2)Google Scholar). Last but not least, clinical findings suggest that antibiotic treatment, at least temporarily, has a beneficial effect on disease activity in patients with CTCL colonized by S aureus (Talpur et al., 2008Talpur R. Bassett R. Duvic M. Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome.Br J Dermatol. 2008; 159: 105-112Google Scholar; Lindahl et al., 2019Lindahl L.M. Willerslev-Olsen A. Gjerdrum L.M.R. Nielsen P.R. Blümel E. Rittig A.H. et al.Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.Blood. 2019; 134: 1072-1083Google Scholar). In addition, the discovery by Lindahl et al., 2019Lindahl L.M. Willerslev-Olsen A. Gjerdrum L.M.R. Nielsen P.R. Blümel E. Rittig A.H. et al.Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.Blood. 2019; 134: 1072-1083Google Scholar that aggressive antibiotic treatment reduces the fraction of malignant T cells in skin lesions colonized by S aureus provides proof-of-concept that clearing and preventing skin colonization by S aureus could be essential to inhibit S aureus–mediated symptoms and disease progression. However, the effect of antibiotics appears to be temporary in most cases, as lesional skin quickly becomes recolonized by S aureus after the antibiotic treatment is discontinued. Although aggressive antibiotic treatment remains relevant in clinically severe and life-threatening S aureus infections, long-term aggressive antibiotic treatment to prevent S aureus skin colonization is neither feasible nor advisable because of the risk of side effects and the development of antibiotic resistance. In fact, high frequencies of skin colonization by methicillin-resistant S aureus have been observed in patients with CTCL and atopic dermatitis. Consequently, there is an urgent need for novel nonantibiotic and highly selective anti-S aureus treatment modalities to control and prevent its harmful effects. A recent study reported that bacteriophage-derived, engineered endolysin can effectively eliminate patient-derived S aureus from colonizing lesional patient skin ex vivo and can block tumor-promoting effects of patient-derived S aureus in CTCL models (Pallesen et al., 2023Pallesen E.M.H. Gluud M. Vadivel C.K. Buus T.B. de Rooij B. Zeng Z. et al.Endolysin inhibits skin colonization by patient-derived Staphylococcus aureus and malignant T-cell activation in cutaneous T-cell lymphoma.J Invest Dermatol. 2023; 143: 1757-1768.e3Google Scholar). This discovery offers hope that novel, selective, nonantibiotic anti-S aureus adjuvant therapies will contribute to improving disease control and prognosis in patients with CTCL, without the risk of antibiotic resistance. Emmanuella Guenova: https://orcid.org/0000-0001-5478-8735 Niels Ødum: https://orcid.org/0000-0003-3135-5624 Niels Ødum has received consulting honoraria from Micreos Pharmeceuticals, and Almirall. Emmanuella Guenova has received consulting fees, payment or honoraria from Helsinn, KIOWA Kirin, Mallinckrodt Pharmaceuticals, Novartis, Recordati Rare Diseases, Sanofi, and Takeda. Characteristics of Staphylococcus aureus Colonization in Cutaneous T-Cell LymphomaJournal of Investigative DermatologyPreviewStaphylococcus aureus (SA) colonization is strongly associated with cutaneous T-cell lymphoma (CTCL) and often leads to fatal bacterial infections (Lindahl et al., 2022). Growing evidence suggests that staphylococcal enterotoxins (SEs), staphylococcal α-toxin, and lipoprotein play important roles in promoting CTCL development and progression (Blümel et al., 2019; Fujii, 2022). Specifically, staphylococcal enterotoxin A (SEA) has been linked to CTCL pathogenesis by targeting multiple cell components within the tumor microenvironment, including malignant T cells, CD8+ tumor infiltrating T cells, and conventional CD4+ T cells (Willerslev-Olsen et al., 2016, 2020, 2021). Full-Text PDF