Role of antigenic stimulation in cutaneous T cell lymphomas

Abstract

Cutaneous T cell lymphoma (CTCL) involves a clonal expansion of malignant cells accumulating in the skin, a primary barrier site. CTCL has long been hypothesized to be caused or perpetuated by chronic antigen stimulation due to unknown exposures. These antigenic triggers, defined as any element that may cause activation of malignant T cells through TCR signaling, have been hypothesized to range from chemicals to microbes. This review covers current evidence supporting chemical and microbial stimuli that may act as antigenic triggers of CTCL and summarizes novel areas of investigation, in which the potential antigenicity of the exposure is still unknown.

INTRODUCTION

Cutaneous T cell lymphomas (CTCL) is a heterogenous group of non-Hodgkin lymphomas (NHL) characterized by infiltration of the skin. Among the various subtypes of CTCL, mycosis fungoides (MF) is the most prevalent, while Sézary syndrome (SS) is a rarer, more aggressive type. CTCL incidence increased three-fold between 1970 to 2000 and is currently estimated between 5.4 to 11.3 cases per one million persons per year (Dobos et al., 2021, Ghazawi et al., 2017, Korgavkar et al., 2013, Ottevanger et al., 2021). Despite the expanding clinical and academic presence of CTCL, its etiology remains elusive. Nonetheless, mounting evidence implicates a potential interplay between antigenic stimuli and oncogenic mutations in both the initiation and progression of CTCL.

In CTCL, the clonal expansion and accumulation of malignant immune cells in the skin, a primary interface with the external environment, begs the question of potential external drivers. These drivers could range from specific environmental triggers to a cutaneous microbial environment that propagates the clonal evolution of CTCL. The pathogeneses of many skin cancers are associated with external agents, such as ultraviolet (UV) radiation, arsenic, human papillomavirus, Merkel cell polyomavirus, and human herpesvirus 8 (Mesri et al., 2010). Likewise, the connection between microbes and hematologic malignancies has been well-established in certain cases (e.g., Helicobacter pylori and gastric MALT lymphoma; Epstein-Barr virus (EBV) and Burkitt’s lymphoma) and has been suggested in others (e.g., the potential contribution of Chlamydia psitacci to ocular adnexal MALT lymphomas) (Chanudet et al., 2006, Lombardi et al., 1987, Wotherspoon et al., 1991). EBV has a complex association with lymphomas of B-, T-, and NK-cell origin that involves dynamic interactions between viral gene expression and cellular oncogenic alterations. Additionally, bacterial influences, such as presence of Staphylococcus aureus in atopic dermatitis, are suggested to incite immune dysregulation and inflammation in the skin, and the pathogenic role of dysbiosis of the gut microbiome in diseases ranging from colorectal, esophageal, and liver cancers to inflammatory skin conditions has been noted (Geoghegan et al., 2018, Widhiati et al., 2022, Zhao et al., 2023).

CTCL has long been hypothesized to be caused or perpetuated by chronic antigenic stimulation. However, recent advances in microbial next-generation sequencing and enhanced epidemiological datasets have renewed interest in this area, enabling a more precise delineation of these contributing factors. Antigenic triggers, defined in this context as any element that activates malignant cells through T cell receptor (TCR) signaling, may include classical antigens presented in an MHC-restricted manner and secreted factors that cause TCR signaling. Signatures of the malignant T cells in CTCL, including clonality, exhaustion / activation, and TCR β chain variable (Vβ) biases, as well as associations to HLA class II alleles, suggest a role for TCR-dependent proliferation and selection in disease development, which likely precedes the accumulation of neoplastic memory cells (Anzengruber et al., 2019, Bahler et al., 1992, Jack et al., 1990, Querfeld et al., 2018, Saulite et al., 2020). Further, clinical observations of the effectiveness of bleach baths and antibiotic treatment support the putative link to microbial triggers, as will be discussed in more detail (Poligone and Querfeld, 2015). This review explores the potential sources of antigenic stimulation, both classical and atypical, that may contribute to CTCL pathogenesis.

PRECIPITATING TRIGGERS OF CTCL

Occupational and environmental exposures

While early case studies suggested a possible role for genetic factors and heredity in CTCL, the exact contributions of genetic versus environmental factors remains to be elucidated. Rare cases of disease-concordant monozygotic twins have been observed (Naji et al., 2001, Schneider et al., 1995), and genetic studies have revealed associations with specific HLA class II alleles (Hodak et al., 2001). Likewise, non-twin familial occurrence of CTCL has also been observed (Hodak et al., 2005). However, a large analysis of 42 twin pairs revealed no instances of both twins having CTCL, thereby suggesting that shared genetics alone has minimal impact on the disease’s occurrence (Odum et al., 2017). Further studies are needed to investigate whether familial CTCL clustering may be related to co-housing and shared familial exposures.

Throughout the past two decades, geographic clustering studies focused on CTCL have identified non-random correlation between increased incidence and areas with extensive industrial presence or with high risk for toxin exposure (Ghazawi et al., 2017, Ghazawi et al., 2018, Litvinov et al., 2015, Moreau et al., 2014). Such geographic clustering has been observed in Pittsburgh, Pennsylvania, a US city with a history of industrial pollution, although patient clusters did not correlate with major industrial hubs in the city. Other significant regions include areas of Texas (Houston, Beaumont, and Tyler), which may be related to the high density of oil refineries and potential radiation pollution (Litvinov et al., 2015, Moreau et al., 2014). Similarly, clustering of CTCL incidence with current or previous industrial areas was observed in Canada over a 20-year period, although the potential impact of patient migration on exposure history in this cohort was less clear (Ghazawi et al., 2017, Ghazawi et al., 2018). In Atlanta, Georgia, areas with elevated concentrations of known environmental toxins, such as benzene and trichloroethylene, were found to be correlated with a higher incidence of CTCL (Clough et al., 2020). While the identification of specific environmental pollutants and the routes by which residents are exposed warrants further study, these studies suggest that environmental exposures occurring during normal life in polluted areas may be a trigger of CTCL.

In addition to ambient environmental exposures, specific occupational or recreational exposures have been implicated in CTCL, including chemicals used in agriculture, ceramics, glass, and paper production (Morales Suárez-Varela et al., 2004, Nguyen et al., 2023). Similarly, epidemiological studies have uncovered associations between NHL incidence and exposure to agricultural pesticides like glyphosate (Donato et al., 2020), manufacturing compounds such as organic solvents, and radiation (Rieutort et al., 2016). Retrospective survey studies of CTCL patients have evaluated more specific exposures, namely petrochemicals, air pollution, pesticides/insecticides, epoxy resins, and plants of the family Compositae; however, the data from these studies are inconclusive regarding whether such exposures increase risk of disease (Fischmann et al., 1979, Tuyp et al., 1987, Whittemore et al., 1989). Importantly, the potential for recall bias presents a possible limitation in these retrospective survey studies, especially considering the attention on certain potential carcinogens as made popular by the media.

Nonetheless, determining if there is a unifying environmental exposure that acts as an antigenic trigger for CTCL is difficult and complex. Limitations to these studies include compounding, multifaceted lifestyle factors; patient migration over time; differences in access to medical care, particularly dermatologists; and the challenges of identifying and quantifying exposures to unknown compounds. For example, one study of CTCL patients across New Jersey revealed a lack of geographical clustering, but a positive relationship between increased local median income and CTCL incidence. The study also revealed that Blacks had the highest incidence rates across income levels, highlighting that disease incidence may be unevenly distributed across different races/ethnicity (Wiese et al., 2023). Other recent studies, controlling for median income or race respectively, have found geographical clustering across Louisiana and Florida, although the implicated chemicals are still unknown (Maghfour et al., 2022, Malachowski et al., 2022). These findings emphasize the need for future studies that incorporate these features, to better elucidate the role of environmental exposures in ways that account for the impact of socioeconomic status and race in community geography.

The question of how potential chemical exposures might contribute to the onset of CTCL remains unresolved. In addition to direct carcinogenic effects, chemical and environmental exposures might instigate antigenic stimulation alone, through modifying a self-antigen, or even by altering HLA molecules to produce an entirely new repertoire of modified antigens (Illing et al., 2012). This concept of chemical antigenicity may be most readily investigated in the context of known personal exposures, such as medications. While various drugs have been studied in CTCL, including alcohol, immunosuppressive regimens, antihistamines, antiepileptics, and antidepressants, current evidence does not suggest that these act as antigenic triggers in CTCL (Morales Suárez-Varela et al., 2001, Pomerantz et al., 2010).

Early studies identified thiazides as a potential trigger of CTCL, a connection proposed to be due to persistent antigenicity and the ability of thiazides to act on the skin, as shown by their infrequent phototoxicity effects (Diffey and Langtry, 1989, Fischmann et al., 1979). One trial investigated hydrochlorothiazide (HCTZ) treatment in CTCL patients and found that a small subset of patients who developed CTCL after beginning HCTZ therapy experienced remission following HCTZ discontinuation, while a few instances of accidental rechallenge elicited disease exacerbation (Jahan-Tigh et al., 2013). Likewise, a single case study of γδ CTCL, diagnosed via immunohistochemistry of the biopsy sample, resolved completely following discontinuation of HCTZ therapy (Allison Pye, 2017). Nonetheless, drug-induced pseudolymphoma may confound diagnosis in these cases (Bendewald, 2012). Additional research must be done to determine the mechanism by which thiazides could act and whether thiazides indeed elicit TCR engagement, thereby contributing to evolution or selection of clonal T cells, in contrast to a more general polyclonal proliferation.

Viral antigens

Despite three decades of continuous investigation, little compelling evidence linking viruses and CTCL has emerged. No associations have been established between CTCL and human T-lymphotropic virus 1/2, which drives development of Adult T cell Leukemia/Lymphoma; EBV, associated with pathogenesis of certain B cell lymphomas; or cytomegalovirus, human herpesvirus 6/7/8, or polyomaviruses, which are associated with cancers such as Merkel cell carcinoma (Fouchard et al., 1998, Mirvish et al., 2011, Novelli et al., 2009). Although immunodeficiency is thought to increase the risk of T cell lymphoma (Biggar et al., 2001, Kerschmann et al., 1995), estimates of human immunodeficiency virus (HIV)-associated CTCL suggest the actual risk is very low (Yang et al., 2022), and analysis of HIV-associated CTCL may be confounded by mischaracterization of HIV-related cutaneous pseudolymphomas (Wilkins et al., 2006). Human simplex virus (HSV) 1/2 and varicella zoster virus (VZV) have been observed frequently in CTCL patients and have also been investigated as potential disease triggers, but these studies are confounded by HSV and VZV latency, as well as their recurrence with local immunosuppression, as may occur in CTCL (Axelrod et al., 1992). Thus, although some of these classic viruses have been linked to oncogenesis, there is no evidence that they play a role in CTCL pathogenesis.

Despite the lack of evidence for an antigenic role of most viruses in CTCL, recent research on human cutavirus (CuV), a parvovirus of the Protoparvovirus genus, has revealed an intriguing new association with CTCL. Studies from France and Finland using a quantitative multiplex PCR approach detected CuV DNA more frequently in skin biopsies of CTCL patients (4 out of 17, and 4 out of 25, respectively) compared to healthy adults (0 out of 21 and 0 out of 98, respectively) – a statistically significant difference in both cohorts (Phan et al., 2016, Väisänen et al., 2019). Interestingly, Väisänen and colleagues also observed CTCL and pre-cancerous CTCL skin biopsies carried higher loads of CuV DNA versus melanoma, sentinel lymph node, and prostate cancer samples (Väisänen et al., 2019). Likewise, recent studies have also found an enrichment of CuV in CTCL patients in Japan, as well as an enrichment of CuV in Finnish patients with nonmalignant plaque parapsoriasis, a common precursor to CTCL (Hashida et al., 2023, Mohanraj et al., 2023). Whether the association between CuV and CTCL is causal or secondary to local immunosuppression remains to be elucidated. In contrast, a study from Italy using real time PCR found no CuV DNA in 55 CTCL samples (Bergallo et al., 2020). Further research into association between CuV infection and CTCL is needed to determine if this virus can impact CTCL pathogenesis, and if it does, whether it can do so via direct oncogenic mechanisms or through antigenic stimulation.

PERPETUATING FACTORS

The concept of microbial antigenic activity playing a prominent role in the progression and perpetuation of CTCL has been central to recent academic discourse regarding CTCL pathogenesis. Providing crucial support to this notion, several cohort studies have demonstrated MF patients with bulky tumor-stage disease can achieve rapid clinical improvement with topical and systemic antibiotics (Lindahl et al., 2021, Talpur et al., 2008). Aggressive systemic therapy in these patients leads to decreased expression of IL-2 high-affinity receptor, diminished STAT3 signaling, and reduced proliferation of malignant T cells in lesional skin (Lindahl et al., 2019). Likewise, the antistaphylococcal and palliative skin “Duvic regimen” can promote clinical improvement, and the effectiveness of bleach baths supports a link to microbial triggers (Lewis et al., 2018, Poligone and Querfeld, 2015). While bacterial triggers have been explored in CTCL, the possibility that bacterial antigens may act as a trigger in CTCL pathogenesis is a robust area of ongoing investigation.

Several bacterial genera and species have been implicated in CTCL progression, with the strongest data supporting a pathogenic role for S. aureus. Culture-based studies have showed CTCL patients have higher rates of skin and nasal colonization by S. aureus compared to healthy controls (Nguyen et al., 2008), and nasal S. aureus colonization rates are highest amongst patients with erythrodermic SS (Talpur et al., 2008). Amidst the broad spectrum of infections affecting CTCL patients, S. aureus causes chronic skin impetiginization that impairs skin barrier integrity and allows for easier entry of other disease-causing microbes into the bloodstream. This predisposition to infection coincides with patients’ baseline immunocompromised status, which is most extreme in advanced stage CTCL by virtue of patients’ dramatically decreased TCR and polyclonal T cell diversity. To that end, retrospective cohort studies have demonstrated S. aureus is the most common instigator of lesional superinfection, bacteremia, and sepsis in CTCL patients (Axelrod et al., 1992, Hooper et al., 2023). Bacteremia and sepsis of any microbial etiology are associated with an overall increased risk of death in CTCL (Allen et al., 2020, Glinos et al., 2023). Interestingly, recent studies also suggest that malignant T cells may induce protein-level changes in the epidermis, causing skin barrier defects that likely increase susceptibility to bacterial infection (Gluud et al., 2023).

While the primary pathogenesis of CTCL is still contingent upon mutations or other aberrant genetic events, various groups have demonstrated S. aureus superantigens (SAgs; e.g., enterotoxin and toxic shock syndrome toxin-1) and pore-forming toxins (e.g., α-hemolysin) influence CTCL disease activity. Early studies revealed staphylococcal SAgs promote T cell hyperproliferation in a polyclonal, Vβ-specific manner (Jackow et al., 1997, Tokura et al., 1992). This SAg-mediated activation of TCR-Vβ chains in CTCL was later noted to occur in not only malignant cells, but also non-malignant tumor-infiltrating T cells; these benign cells then stimulate further tumor cell proliferation via MHC II activity, strengthening the malignant T cell phenotype and accelerating disease progression (Willerslev-Olsen et al., 2013, Woetmann et al., 2007). Multiple reports have also demonstrated that S. aureus enterotoxins trigger malignant and benign T cell crosstalk that leads to STAT3-mediated IL-10 production by malignant cells (Krejsgaard et al., 2017, Willerslev-Olsen et al., 2016). This toxigenic STAT3 activation and the expression of related cytokines may contribute to the aberrant JAK/STAT activity that promotes immune dysregulation and malignant T cell survival (Krejsgaard et al., 2017, Sommer et al., 2004). Furthermore, gnotobiotic studies in a mouse model of CTCL driven by conditional hyperactivation of STAT3 revealed that bacterial triggers play a critical role in progression of malignant disease on a genetic background predisposed to CTCL (Fanok et al., 2018).

Toxins also impact CTCL disease activity, although these mechanisms act through exacerbation of antigen- and SAg-dependent effects of S. aureus rather than direct antigenicity. Willerslev-Olsen and colleagues showed staphylococcal enterotoxin A induces tumor cells to upregulate IL-17, which promotes angiogenesis and lymphangiogenesis (Willerslev-Olsen et al., 2016). Additionally, high levels of IL-17F expression in CTCL lesion skin has been found to correlate with risk of disease progression (Krejsgaard et al., 2013). More recently, staphylococcal α-hemolysin – a pore-forming exotoxin produced by 95% of S. aureus strains (Ahmad-Mansour et al., 2021) – was shown to promote tumor survival in CTCL. Concurrent to the elimination of anticancer cytotoxic CD8+ T cells by α-hemolysin, malignant T cells demonstrate toxin resistance via the downregulation of its surface receptor (Blümel et al., 2020, Blümel et al., 2019).

Interestingly, recent data suggest that species beyond S. aureus may also influence CTCL pathogenesis. S. epidermidis and S. warneri are known to curtail the population size of S. aureus, which could restrict its oncogenic activity and may explain why lesional and non-lesional predominance of these species is associated with phototherapy-responsive CTCL (Hooper et al., 2022a). A comparison of the skin microbiome between CTCL patients and healthy controls using whole-genome shotgun sequencing (WGS) revealed that lymphoma-affected skin may contain enriched populations of S. argenteus (Salava et al., 2020). This staphylococcal species, previously thought to be hypovirulent, actually expresses α-hemolysin at levels four- to six-times that of S. aureus (Holt et al., 2011, Johansson et al., 2019). Possibly, bacterial toxins and the magnitude of their production could be more important to CTCL pathogenesis than species’ overall population size or even relative abundance. Dehner and colleagues found that Bacillus safensis, a rare skin commensal, precipitates a proliferative response of CLA+ CCR4+ CD4+ skin-homing T cells and related production of proinflammatory cytokines, including IL-17A, IFNγ, and IL-10 (Dehner et al., 2022). Even in the absence of high levels of B. safensis on CTCL skin, Bacillus-induced IL-10 production may contribute to malignant T cell immune evasion by inhibiting benign T cells (Abraham et al., 2011, Krejsgaard et al., 2017). Other Bacillus species could also promote this antigenic pathway, such as B. pumilus, a species with phylogenetic and functional similarity to B safensis and found to be abundant in both lesional and non-lesional skin of some CTCL patients (Salava et al., 2020). However, as enriched populations of Bacillus species have not been seen in other CTCL microbiome studies, these findings may be specific to only certain populations of CTCL patients. Dehner and colleagues suggested the oncogenic behavior of B. safensis may work synergistically with the toxin-producing activity of S. aureus on CTCL-affected skin, but this hypothesis remains to be validated (Dehner et al., 2022).

Lastly, unique microbial profiles have been identified in the skin microbiomes of CTCL patients that could also explain differences in disease behavior, such as symptomatology, disease progression, or therapy refractoriness (Harkins et al., 2021, Hooper et al., 2022a, Hooper et al., 2022b, Hooper et al., 2022c, Salava et al., 2020, Zhang et al., 2022). For example, as identified using 16S ribosomal RNA (rRNA) sequencing, the CTCL skin microbiome can exhibit phenotypic-specific patterns: erythematous and painful lesions are associated with enriched Staphylococcus abundance, pruritic lesions with increased Sphingomonas and Parvimonas, and thick lesions with higher prevalence of Paracoccus (Zhang et al., 2022). Shifts in skin microbiome signatures appear to correlate with CTCL stage (Harkins et al., 2021), emphasizing the likelihood that bacteria influence CTCL flares and progression, and the recent demonstration that nbUVB responders and non-responders have distinct skin microbiomes both before and after treatment suggests bacteria may impact disease responsiveness to certain treatments (Hooper et al., 2022a). While these findings do not specify if a bacterial antigen exists in CTCL, they do suggest that modulation of cutaneous microbiota – in population size, relative abundance, or even superantigen production – can shift the antigenic-immune milieu underlying CTCL lesional activity (Hooper et al., 2022a, Yoshimura-Mishima et al., 1999).

Characterization of the CTCL nasal and gut microbiota is in its infancy: preliminary data has linked CTCL with altered bacterial communities in these niches, but data elucidating the direct pathogenic influence of these microbiomes has yet to be reported (Hooper et al., 2022b, Hooper et al., 2022c). Still, multiple groups have discussed the possibility of a feed-forward loop of inflammation and pro-oncogenic antigenic activity between gut dysbiosis and CTCL, amongst other cancers and inflammatory skin diseases (Codoñer et al., 2018, Hooper et al., 2022b, McCarthy et al., 2022, Rajagopala et al., 2020, Song et al., 2015, Yamamoto et al., 2013). More specifically, the tumorigenic potential of gut flora has been associated with pro-inflammatory shifts in metabolite production and disruption of the gut epithelial barrier that permits translocation of virulent microbes into the bloodstream – in short, the complex crosstalk shared by the gut microbiome and the host immune system (Vivarelli et al., 2019). Comparison of the gut microbiome of CTCL patients versus healthy controls using 16S rRNA sequencing identified significantly reduced relative abundance of anti-inflammatory, butyrate-producing species (e.g., Bidifobacterium, Lactobacillus, Anaerotruncus) and simultaneous enrichment of pro-inflammatory, lipopolysaccharide-producing species like Proteobacteria in patient samples (Hooper et al., 2022b). These changes likely forward oncogenesis in part by tipping the balance of the gut-immune microenvironment to one of hyper-stimulating, pro-tumorigenic conditions. Furthermore, lipopolysaccharide activates host cell TLR4 receptors, and TLR4 activity in the CTCL microenvironment has been linked to tumor growth and disease-associated immunosuppression (Jarrousse et al., 2006, Shah et al., 2021). Additionally, the ability of butyrate, a short-chain fatty acid, to act as a histone deacetylase inhibitor promotes a general anti-cancer effect and mirrors the mechanism of action of romidepsin and vorinostat – important treatment options for advanced CTCL (Wei et al., 2016). Enriched Prevotellaceae and Bacteroidaceae families in the CTCL gut microbiome may also promote local and distant Th17 differentiation, thereby stimulating chronic IL-17 release, inflammation, and related malignancy (Calcinotto et al., 2018, Rutkowski et al., 2015). Whether changes in the gut microbiome can contribute directly to CTCL pathogenesis or are merely epiphenomena of the disease, the influence of gut-immune and gut-skin axes should not be omitted from the broader narrative of CTCL antigenic cascades and warrants further investigation.

FUTURE DIRECTIONS

As discussed in this review, CTCL has long been hypothesized to be precipitated or perpetuated by chronic antigen stimulation, wherein supposed antigens range from environmental and occupational chemical exposures to cutaneous microbes and their secreted products (Figure 1). Current evidence supports a role of S. aureus in CTCL, likely through a combination of antigenic stimulation by secreted superantigens, with additional inflammation and immune dysregulation induced by toxins, and possibly also the release of endogenous neo-antigens. Other skin microbes, including human cutavirus and Bacillus species, merit further study as potential antigens. Unbiased studies should continue to identify skin microbial profiles that differentiate patient samples and could feasibly stimulate disease activity. Additionally, several epidemiological studies support the hypothesis that environmental factors may contribute to CTCL, but there is notable heterogeneity across the implicated chemicals and their postulated mechanisms of antigenicity. While more research is required to delineate the relationship(s) between possible chemical triggers and CTCL pathogenesis, efforts to distill the impact of socioeconomic status and race in geographic clustering, occupation patterns, and CTCL incidence will improve the quality of these data.

Figure 1:

Hypothesized pathogenesis of cutaneous T cell lymphoma (CTCL), with routes of antigenic drivers. CTCL may arise from chronic antigen stimulation, either through classical pathways via dendritic cells (DCs), or through direct stimulation by staphylococcal superantigens. This stimulation may trigger expansion and selection of the malignant clone, which likely co-occurs with oncogenic genetic alterations.

It is also important to step back and question if there are other possible antigens that should be explored. One such possibility is that the stimuli discussed above may contribute to the release of, or sensitization to, skin antigens. This interaction could occur through chemical or microbial modification of self-proteins in the skin, or the novel release or presentation of skin antigens in response to the exposure. For example, S. aureus and other skin pathobionts may be perpetuating disease through chronic skin damage and skin antigen release, in addition to the disease exacerbation achieved by secreted bacterial products. Chemical exposures, including environmental contacts or perhaps iatrogenic influences, may cause chronic damage to the skin that releases skin antigens and promotes sensitization, or alternately, that directly modifies native skin peptides. Like all putative triggers, skin damage and skin antigens may only play a role in a small portion of CTCL cases, but research should be pursued to determine if the skin itself is ever the origin of antigenic stimulation in CTCL.

Additionally, future investigations should aim to explain the antigenic dynamics of different microbial communities on both intra-community and inter-community bases. Further research may elucidate the impact of microbial signaling, for example whether quorum sensing of cutaneous S. aureus by other Staphylococcus species influences CTCL disease activity or progression. Likewise, it will be crucial to determine if chemical exposures, environmental or iatrogenic, interplay with microbial communities to modulate their influence on CTCL. Lastly, efforts to further study the gut-skin and gut-immune connections and related microbiota in CTCL are needed to clarify what role, if any, these ecosystems play in malignant disease.

Current evidence suggests that antigen-driven proliferation and/or selection may play a role in tumor evolution. Future studies should investigate the chronological progression and combinatorial effects of random mutations, exposure-induced mutations, and antigenic TCR stimulation in the pathogenesis of CTCL. If antigen-driven selection plays a crucial role in CTCL pathogenesis, how does this occur, and how does antigen-driven clonal proliferation and selection influence the mutations occurring in malignant cells? Lastly, further studies are needed to define how the proliferation of malignant T cell in the skin contributes to disease evolution and continual accumulation of genetic aberrations. In particular, persistent cutaneous exposures (i.e., carcinogens, UV radiation, or antigens) may promote initial disease pathogenesis or stage-specific disease exacerbation as has been suggested by a number of recent studies (Herrera et al., 2021, Jones et al., 2021). While UV exposure and mutational signatures are implicated in CTCL pathogenesis, paradoxically, narrowband UVB exposure is a mainstay therapy. Phototherapy slows disease progression and extends survival times, despite theoretically increasing the risk of mutations (Hoot et al., 2018). Therefore, further research is needed to resolve this paradox.

The inherent complexity of human studies, characterized by multifactorial exposure histories and the diversity of molecular disease, presents significant challenges to our current understanding of CTCL. While this review does not delve into the nature of aberrant genetic events associated with CTCL, it is important to note that these oncogenic mutations and translocations likely emerge before and during the expansion of a malignant clone. Compelling evidence supports the premise of TCR-driven stimulation as a pivotal player in the pathogenesis and progression of CTCL. Deciphering the enigma of CTCL pathogenesis is vital to the development of disease-specific therapies and management strategies. Such understanding will augment our ability to more effectively curb oncogenic disease and stave off complications associated with advanced stages of the disease.

Abbreviations:

CTCL

cutaneous T cell lymphoma

UV

ultraviolet

EBV

Epstein-Barr virus

TCR

T cell receptor

Vβ

TCR β chain variable

HCTZ

hydrochlorothiazide

HIV

human immunodeficiency virus

HSV

human simplex virus

VZV

varicella zoster virus

WGS

whole-genome shotgun sequencing

rRNA

ribosomal RNA

SAg

superantigen

Data Availability Statement

No datasets were generated or analyzed during the current study.