Mini Review ARTICLE
Update on Biology of Cutaneous T-Cell Lymphoma
- 1Johns Hopkins University School of Medicine, Baltimore, MD, United States
- 2Departments of Oncology and Medicine, Johns Hopkins University, Baltimore, MD, United States
- 3Department of Dermatology, Johns Hopkins University, Baltimore, MD, United States
Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.
Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of lymphoid malignancies derived from skin-homing T cells. The incidence rate of CTCL is 6.4 per million persons and has experienced increases in recent years in part due to better diagnosis (1). Highest incidence rates are seen among African Americans and older individuals, with a four-fold increase in incidence of patients over 70 (2, 3). Mycosis fungoides (MF) is the most common form of CTCL characterized by skin-homing CD4+ T cells. Sezary syndrome (SS) is an aggressive CTCL variant with varying levels of clonal lymphocytes in the blood. MF and SS together account for more than 50% of all CTCL cases (4). Diagnosis of CTCL is challenging due to the polymorphic nature of disease presentation, and a lack of a single definitive diagnostic procedure. Management of limited-stage MF involves more conservative approaches such as skin directed therapies while advanced-stage MF/SS patients are often treated with targeted and systemic chemotherapies, which are often short-lived and associated with adverse reactions (1). Large cell transformation (LCT) is a complication found in advanced-stage MF/SS that is histologically defined by the presence of large, atypical lymphocytes exceeding 25% of lymphoid infiltrate and is historically associated with significantly lower median survival compared to non-transformed MF (5). In addition, expression of CD30 antigen does not manifest in significant prognostic significant differences (6). However, brentuximab vedotin, a CD30 targeting antibody-drug conjugate, has demonstrated significant clinical response in variable CD30+ CTCL patients (7, 8).
Beyond differences in clinical presentation, the biology of malignant T cells in MF and SS are thought to be at least in part distinct due to expression of cell surface markers consistent with skin resident effector memory T cells and central memory T cells, respectively (9). However, recent single-cell profiling studies reveal phenotypic plasticity and tumor heterogeneity, suggesting that MF and SS may belong to the same disease spectrum. The molecular and cellular biology of this spectrum of malignancies has yet to be fully decoded. In this review, we will discuss advances in understanding the genomic landscape of CTCL with emphasis on recent NGS studies in further elucidating the pathogenesis of MF and SS. We acknowledge that the fast pace of evolving technologies, such as single-cell profiling, will provide further insights to patient-specific tumor biology.
Origin of Malignant T Cells
External Risk Factors
Despite isolated case series of familial mycosis fungoides (10) and links to potential HLA alleles (11, 12), there is no concrete evidence for genetic predisposition. Additionally, infectious agents such as viruses, viral particles (13–15), environmental, geographical (16) or occupational exposure (17) have been contemplated to be triggers for the rise of CTCL but a strong link has not been identified.
Bacterial infections, particularly with staphylococcus aureus, are frequently noted in patients with CTCL and antibiotic therapy usually results in clinical improvement (18–20) Housing mice with CTCL-like features in germ-free conditions led to attenuated tumor burden which was reversible when co-housed with conventional mice (21). A recent prospective study examining 8 patients with advanced-stage CTCL found that transient antibiotic treatment is associated with a decrease in fraction of neoplastic T cells, decreased cell proliferation and a decreased in STAT3 signaling (22). While the mechanistic role is unclear, these data indicate that the commensal microbiome may play a role in malignant T cell transformation and consequently may serve as a therapeutic target.
Tumor Microenvironment and Dysregulated Cytokine Signaling
T cell receptors (TCRs) recognize and bind to a specific antigen presented by the major histocompatibility complex molecule (MHC); this interaction induces a cascade of phosphorylation and gene expression that results in T cell survival and proliferation. The hyperactivity of the TCR pathway, either by genetic alteration (23–25) and/or continuous contact with antigen presenting cells (26, 27) can result in robust proliferation and continuous activation of T cells leading to disease progression. Malignant T cell clones in MF can be traced to peripheral blood by TCR sequencing and the heterogeneity of malignant T cells between skin lesions might be partially attributed to variation in seeding patterns by peripheral blood (28). The growth and viability of the CTCL cell is partly dependent on direct contact with immature dendritic cells (DC), through interaction between CD40 located on DC and CD40 ligand located on CTCL cells (26). Macrophages and mast cells are also investigated for the roles they play in the tumor microenvironment. In vivo mouse studies demonstrated slower rates of progression of human CTCL tumor cells in mice depleted of mast cells (29) and macrophages (30). The malignant T cells also facilitate shaping the tumor microenvironment that is supportive of disease progression. Multiple ligand/receptor interactions, including VEGF/VEGFR (31) and CXCR4/CXCL12 (32), have been characterized for their role in development of a vascular niche conducive to growth of neoplastic T cells. Further research is needed for potential utilization of these vascular niche factors in improving diagnosis and targeted anti-angiogenic therapy. Malignant T cells also secrete galectin-1 and−3, which have been linked to decreased skin barrier function and uncontrolled epidermal proliferation (33), which explains the increased incidence of bacterial skin infections observed in CTCL patients. The functional state of T cell is crucial in the dynamic state of tumor microenvironment. In cancer, T cells operate in a chronic inflammatory state and ultimately enter a hypo-responsive state called T cell exhaustion which is in part characterized by expression of inhibitory receptors (34). Indeed, malignant T cells derived from patients across all CTCL stages display increased expression of inhibitory receptors including PD-1 (35–37), CTLA-4 (38), and LAG-3 (37). The role of inhibitory receptors in T cell exhaustion implies that they can be targeted to effectively reinvigorate effector T cells. Nivolumab (anti-PD-1) was found to be well-tolerated patients with relapsed or refractory hematologic malignancy, which included patients with MF (39). More recently, a multicenter phase II trial of pembrolizumab (anti-PD-L1) led to favorable outcomes in patients with advanced MF or SS (40). In 2018, the FDA approved Mogamulizumab (anti-CTLA-4) for treatment of relapsed and refractory MF and SS, after a randomized, multicenter phase III clinical trial revealed superior investigator-assessed progression-free survival compared to vorinostat (41).
Investigation of the role of cytokine profile in CTCL stemmed from the observation that atopic dermatitis, a classically Th2-skewed disease, is more prevalent in family history of MF patients (42). PBMCs from SS patients of various stages revealed decreased IL-4, IL-2, and IFN-γ, suggesting that malignant T cells in CTCL resemble the cytokine profile found in Th2 cells (43). Th1 pattern, found to be prevalent in early stage of the disease, may allow antitumor response to local disease. In later stage, there is Th2 and Th17 bias with global depression in cytokine expression, which may signify loss of immune function and T cell exhaustion (44). Gata-3 and JunB, Th2 cells-specific transcription factors, are expressed starting in early disease (45). Induction of Th2-dominant biology is partially linked to expression of extracellular matrix proteins periostin and thymic stromal lymphopoietin (TSLP) by dermal fibroblasts, which subsequently activates release of Th2-specific cytokines in CTCL cells (46).
The immune responses that dictate CTCL progression or inhibition are largely unknown and our understanding is complicated by conflicting results in the literature. For example, pro-inflammatory responses, such as Th17 are thought to promote tumor progression and limit anti-cancer Th1 response (47). Recently, a few case series have shown that TNF-inhibitors and IL-17 inhibitors promoted the development or progression of MF in patients with inflammatory bowel disease, rheumatoid arthritis or misdiagnosed psoriasis (48). Contrary to previous reports, these results suggest that inhibition of Th17 mediated immune responses lead to CTCL disease progression.
On the other hand, regulatory T cells (Tregs) have been associated with Sezary syndrome and are thought to be an indicator of poor outcome (49). However, a recent single-cell profiling study of CTCL identified Treg transcription factor Foxp3 as the strongest predictor of early rather than late-stage Sezary syndrome (50). These data indicate that tumor FoxP3 expression may suppress CTCL disease rather than promote progression as previously thought. Therefore, it is crucial to investigate the factors that drive Th17 and Treg immunity in CTCL to better understand the mechanisms that affect disease outcome.
Our current knowledge on CTCL immunophenotype, cytokine profile and its interactions within the host immune system denote an intricate tumor microenvironment and present numerous potential targets for therapy.
Genomic Landscape of CTCL
In the past few years, multiple groups have applied deep sequencing techniques including whole genome and whole exome sequencing to explore the genomic landscape alterations in cutaneous lymphoma (23–25, 51–53). These results have broadened our horizon in the understanding of the pathogenesis of this heterogeneous group of malignancies by identification of new somatic mutations, and common mutagenic pathways.
TP53 is a tumor suppressor, which responds to DNA damage and other stress signals and is often dysregulated in cancer (54). While a unifying oncogenic driver is absent, TP53 is a notable tumor suppressor in CTCL with a somatic mutation (23) and gene deletion (24, 25) on chromosome 17p detected in 19 and 37% of studied CTCL patients, respectively (55). However, TP53 mutation status does not endow any changes in prognosis in primary SS patients (56). The constitutive activation of nuclear factor kappa B (NF-κB) pathway, located downstream of TCR signaling, has been implicated to play a key role in tumor resistance to apoptosis in CTCL (57). Recent genomic sequencing by multiple groups have reported on alterations in PLCG1 (58), CARD11 (25), TNFRSF1B (23) and KIT (55) that are involved in NF-κB pathway. These alterations are involved in regulating T cell survival and proliferation and/or control transcriptional programs downstream of key T cell signaling. The involvement of the NF-κB pathway served as a rationale for the potential use of bortezomib, an inhibitor of NF-κB signaling, which exhibited 67% overall response rate with acceptable drug tolerability in a phase II clinical trial (59).
To address the low incidence rate of CTCL and small patient cohorts with variations in geographic or subtype origin found in most NGS studies, Chang et al. created an integrated CTCL genomic dataset by collecting and re-analyzing raw genomic data of 139 patients with CTCL from seven different sequencing studies of MF/SS (55). Consolidation of previous NGS cohorts improved statistical power and revealed insights to specific patterns of genetic aberrations. TP53 mutations were found to be mutually exclusive from NF-κB pathway gene mutations, indicating that tumor variants might arise from distinct genetic backgrounds. Moreover, mutual exclusivity was observed within the NF-κB pathway genes, suggesting that CTCL tumorigenesis may be triggered by one pathway alone. Cases that did not carry p53 or NF-κB mutational changes did not have any other significant abnormalities, indicating that other important changes in the transcriptome or epigenome may have a major role in tumorigenesis.
In addition to the NF-κB pathway, the JAK3/STAT3 signal transduction pathway is also well-characterized for its role in survival and proliferation of malignant T cells (60–62). Genomic studies have shown that gain of function point mutations and copy number gains in this pathway are frequent and correlate with gene expression of STAT3 and increased expression of pro-inflammatory cytokines IL17 and IL22, downstream targets of STAT3 activation that likely play a role in tumor progression (25, 63). In a mouse model of CTCL, transgenic STAT3 hyper-activation in T cells was linked to IL-17 and IL-22 expression and phenotypic features of CTCL (21, 64). Staphylococcal enterotoxin A (SEA) has been shown to drive IL-17 expression through a JAK3/STAT3-dependent pathway in malignant T cells when co-cultured with non-malignant T cells, suggesting that SEA-driven cross talk between malignant and non-malignant T cells are needed for oncogenic activation of STAT3 (64).
Beyond somatic mutations characterized previously, genes may also be amplified or deleted due to somatic copy number variants (SCNVs). Compared to other cancers, CTCL is unique in that it harbors a disproportionately high number of SCNV compared to somatic mutations (24). In addition to 17p deletion involving TP53, other tumor suppressors such as RB1, PTEN and CDKN1B have been reported, along with amplification of STAT3 (17q) and MYC (8q) (23–25, 65–67).
Epigenetic abnormalities have been recognized for their role in altering gene expression of oncogenes and tumor suppressors and ultimately contributing to malignant cell transformation in cancer (68). Both hypo-methylation and hyper-methylation signatures have been observed in CTCL. DNMT3A, a gene encoding a methyltransferase, is often mutated or deleted in CTCL (55), signifying that genetic aberrations may underlie epigenetic dysregulation. The association between DNMT3A and mutated genes highlights the importance of integrating findings from sequencing studies and epigenetic findings. Histone deactylases (HDACs) remodel chromatin architecture by removing acetyl groups from histones and have been characterized as a therapeutic target in cancer (69). Vorinostat (70) and Romidepsin (71) inhibit HDACs which leads to gene expression of cell cycle regulators and promotes tumor cell apoptosis.
MiRNAs are non-coding RNA involved in epigenetic mechanisms that are implicated in essential cellular processes (72). The miRNA expression profile has been investigated through different CTCL populations. Increased expression of miR-213, miR-486, and miR-21 were proposed to promote apoptotic resistance in CTCL cell lines (73). Notably, multiple groups have identified miR-155 for its role in pathogenesis of MF (74–76). Later, a causal link was established between JAK/STAT signaling and expression of miR-155 and its host gene BIC (B cell integration cluster), implying that STAT5/BIC/miR-155 can be targeted for therapy (77). MiR-155 inhibitors have been assessed in phase I-II clinical trials for their safety, tolerability and clinical activity with encouraging results (78, 79). MiRNAs may also play a role in predicting prognosis, with multiple groups demonstrating that a panel of miRNAs could be used to effectively stratify patients based on prognosis (80, 81). These types of prognostic markers must be validated in large multi-centered, ideally prospective cohort, studies. While many miRNAs have been implicated in CTCL, further research is needed to delineate the mechanisms in which miRNAs are deregulated and how it impacts disease progression.
Emerging technologies, such as transcript—index ATAC-seq allows researchers to interrogate epigenetic signatures indexed by TCR sequence-based T cell clonality, further refining single-cell resolution in dissecting tumor heterogeneity of CTCL (82).
Emerging Frontiers in CTCL
Emerging technologies in NGS allows researchers to interrogate the DNA sequence and transcriptomes of tumors at the resolution of single cells and has provided an unprecedented view of cellular processes. These advances in technology will rapidly evolve our understanding of tumor transformation and progression.
Single cell RNA-sequencing provides an in-depth view of gene expression profile of each tumor cell as well as an insightful perspective of major cellular components in relation to the tumor microenvironment. The heterogeneity of tumors between patients with CTCL has been well-documented at a clinical and molecular level in the literature. This knowledge has been further cemented by striking distinct gene expression profiles seen in advanced CTCL patients (83). Nevertheless, Gaydosik et al. also identified a 17-gene expression signature that was common between highly proliferative tumor cells in all samples. Interestingly, these signatures overlap with expression of TOX, a previously reported marker for identifying malignant lymphocytes in CTCL (83). Others have utilized single-cell sequencing in conjunction with artificial intelligence (AI)-based learning to create a framework that broadens the clinical applicability of their results in CTCL (50).
Using a single-cell flow cytometry-based assay, Buss et al. isolated malignant cells from 8 treatment-naive patients with SS and assessed the expression of 240 surface antigens and single-cell RNA sequencing for 110 T-cell-relevant genes. Based on surface antigen expression, malignant T cells were divided into distinct subpopulations and exhibited different sensitivities to HDACi treatment (84). The presence of multiple subpopulations with variable sensitivity to a single agent lends further support for the need for combination treatments that are informed by the patient's unique malignant clonal characteristics. The synergistic epigenetic-modulatory effect of histone acetylation of DNA demethylation results in global CpG methylation alterations as well as reexpression of tumor suppressor genes that was not achieved by single agent treatments (85). Preclinical and clinical investigations have demonstrated the combinatorial use of different epigenetic modulators together or in combination with other treatments (85–90).
Mutual exclusivity in CTCL reported by Chang et al. (55) as well as single-cell RNA sequencing analysis may contribute to the basis for molecular subtyping of the disease similar to other hematologic malignancies such as systemic diffuse large B cell lymphoma (DLBCL) (91) or acute leukemia (92). Combination approaches in therapy targeting multiple signaling pathways and clonal subpopulations can lead to unprecedented improvements in survival and quality of life.
Emerging technologies are further refining single-cell resolution in dissecting tumor heterogeneity of CTCL. Applications of these technologies could enable novel therapies or treatment strategies that have previously been deemed unlikely in CTCL. One such example is chimeric antigen receptor (CAR) T cell therapy, which primes the patient's own T cells to activate upon recognition of a tumor-specific antigen (93). CAR T therapies targeting CD19 in B cell malignancies led to durable remissions for refractory B-ALL (94) and DLBCL (95) patients. In contrast, immunophenotypic methods yield high overlap in surface markers between malignant and normal T cells, which presents a major challenge in targeting cancerous cells. Future studies could reveal more subtle phenotypic differences in T cells as NGS technologies enables higher resolution of clonotypic T cells.
We have yet to identify a major oncogenic driver or a constellation of genetic and epigenetic alterations that lead to malignant clonal T cell expansion seen in CTCL patients. However, recent NGS data including single cell sequencing have identified genetic aberrations in major signaling pathways and epigenetic components that play an important role in pathogenesis of CTCL. They have provided biomarker signatures that could be utilized in the future to identify early disease, predict disease progression, and tailor treatments to individual patients. It is important to ask the right type of research questions when performing such studies to extract relevant data and improve clinical outcomes. Further understanding of tumor biology in CTCL is imperative in developing patient-specific treatment with minimal side effects, a cornerstone of precision medicine. We are entering a new area of discovery that will optimize our management for this heterogeneous group of malignancies.
ZP and SR performed literature search and wrote most parts of the manuscript. SS performed literature search and wrote some parts of the manuscript. SR conceived the framework of this review article, provided insights, and edited the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
3. Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International society for cutaneous lymphomas/European organisation for research and treatment of cancer staging proposal. J Clin Oncol. (2010) 28:4730–9. doi: 10.1200/JCO.2009.27.7665
4. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood. (2009) 113:5064–73. doi: 10.1182/blood-2008-10-184168
5. Salhany KE, Cousar JB, Greer JP, Casey TT, Fields JP, Collins RD. Transformation of cutaneous T cell lymphoma to large cell lymphoma. A clinicopathologic and immunologic study. Am J Pathol. (1988) 132:265–77.
6. Arulogun SO, Prince HM, Ng J, Lade S, Ryan GF, Blewitt O, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood. (2008) 112:3082–7. doi: 10.1182/blood-2008-05-154609
7. Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. (2015) 33:3759–65. doi: 10.1200/JCO.2014.60.3787
8. Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and sézary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. (2015) 33:3750–8. doi: 10.1200/JCO.2014.60.3969
9. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. (2010) 116:767–71. doi: 10.1182/blood-2009-11-251926
10. Hodak E, Klein T, Gabay B, Ben-Amitai D, Bergman R, Gdalevich M, et al. Familial mycosis fungoides: report of 6 kindreds and a study of the HLA system. J Am Acad Dermatol. (2005) 52(3 Pt 1):393–402. doi: 10.1016/j.jaad.2003.12.052
12. Jackow CM, McHam JB, Friss A, Alvear J, Reveille JR, Duvic M. HLA-DR5 and DQB1*03 class II alleles are associated with cutaneous T-cell lymphoma. J Invest Dermatol. (1996) 107:373–6. doi: 10.1111/1523-1747.ep12363352
13. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. (1980) 77:7415–9. doi: 10.1073/pnas.77.12.7415
14. van der Loo EM, van Muijen GN, van Vloten WA, Beens W, Scheffer E, Meijer CJ. C-type virus-like particles specifically localized in langerhans cells and related cells of skin and lymph nodes of patients with mycosis fungoides and Sezary's syndrome. A morphological and biochemical study. Virchows Arch B Cell Pathol Incl Mol Pathol. (1979) 31:193–203. doi: 10.1007/BF02889936
15. Morales MM, Olsen J, Johansen P, Kaerlev L, Guenel P, Arveux P, et al. Viral infection, atopy and mycosis fungoides: a European multicentre case-control study. Eur J Cancer. (2003) 39:511–6. doi: 10.1016/S0959-8049(02)00773-6
16. Litvinov IV, Tetzlaff MT, Rahme E, Habel Y, Risser DR, Gangar P, et al. Identification of geographic clustering and regions spared by cutaneous T-cell lymphoma in Texas using 2 distinct cancer registries. Cancer. (2015) 121:1993–2003. doi: 10.1002/cncr.29301
17. Fischmann AB, Bunn PA, Guccion JG, Matthews MJ, Minna JD. Exposure to chemicals, physical agents, and biologic agents in mycosis fungoides and the Sézary syndrome. Cancer Treat Rep. (1979) 63:591–6.
18. Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion. Blood. (1997) 89:32–40. doi: 10.1182/blood.V126.96.36.199_32_40
19. Talpur R, Bassett R, Duvic M. Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sezary syndrome. Br J Dermatol. (2008) 159:105–12. doi: 10.1111/j.1365-2133.2008.08612.x
20. Tokura Y, Yagi H, Ohshima A, Kurokawa S, Wakita H, Yokote R, et al. Cutaneous colonization with staphylococci influences the disease activity of Sezary syndrome: a potential role for bacterial superantigens. Br J Dermatol. (1995) 133:6–12. doi: 10.1111/j.1365-2133.1995.tb02485.x
21. Fanok MH, Sun A, Fogli LK, Narendran V, Eckstein M, Kannan K, et al. Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of cutaneous T-cell lymphoma. J Invest Dermatol. (2018) 138:1116–25. doi: 10.1016/j.jid.2017.10.028
22. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, Nielsen PR, Blümel E, Rittig AH, et al. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood. (2019) 134:1072–83. doi: 10.1182/blood.2018888107
23. Ungewickell A, Bhaduri A, Rios E, Reuter J, Lee CS, Mah A, et al. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat Genet. (2015) 47:1056–60. doi: 10.1038/ng.3370
25. da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, et al. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat Genet. (2015) 47:1465–70. doi: 10.1038/ng.3442
26. Berger CL, Hanlon D, Kanada D, Dhodapkar M, Lombillo V, Wang N, et al. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood. (2002) 99:2929–39. doi: 10.1182/blood.V99.8.2929.h8002929_2929_2939
27. Krejsgaard T, Lindahl LM, Mongan NP, Wasik MA, Litvinov IV, Iversen L, et al. Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover. Semin Immunopathol. (2017) 39:269–82. doi: 10.1007/s00281-016-0594-9
28. Iyer A, Hennessey D, O'Keefe S, Patterson J, Wang W, Wong GK, et al. Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma. Blood. (2019) 134:1517–27. doi: 10.1182/blood.2019002516
29. Wu X, Schulte BC, Zhou Y, Haribhai D, Mackinnon AC, Plaza JA, et al. Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. J Invest Dermatol. (2014) 134:2814–22. doi: 10.1038/jid.2014.206
30. Rabenhorst A, Schlaak M, Heukamp LC, Förster A, Theurich S, von Bergwelt-Baildon M, et al. Mast cells play a protumorigenic role in primary cutaneous lymphoma. Blood. (2012) 120:2042–54. doi: 10.1182/blood-2012-03-415638
31. Miyagaki T, Sugaya M, Oka T, Takahashi N, Kawaguchi M, Suga H, et al. Placental growth factor and vascular endothelial growth factor together regulate tumour progression via increased vasculature in cutaneous T-cell lymphoma. Acta Derm Venereol. (2017) 97:586–92. doi: 10.2340/00015555-2623
32. Kremer KN, Dinkel BA, Sterner RM, Osborne DG, Jevremovic D, Hedin KE. TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTC. Blood. (2017) 130:982–94. doi: 10.1182/blood-2017-03-770982
33. Thode C, Woetmann A, Wandall HH, Carlsson MC, Qvortrup K, Kauczok CS, et al. Malignant T cells secrete galectins and induce epidermal hyperproliferation and disorganized stratification in a skin model of cutaneous T-cell lymphoma. J Invest Dermatol. (2015) 135:238–46. doi: 10.1038/jid.2014.284
35. Wada DA, Wilcox RA, Harrington SM, Kwon ED, Ansell SM, Comfere NI. Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sézary syndrome. Am J Hematol. (2011) 86:325–7. doi: 10.1002/ajh.21960
36. Cetinözman F, Jansen PM, Vermeer MH, Willemze R. Differential expression of programmed death-1 (PD-1) in Sézary syndrome and mycosis fungoides. Arch Dermatol. (2012) 148:1379–85. doi: 10.1001/archdermatol.2012.2089
37. Querfeld C, Leung S, Myskowski PL, Curran SA, Goldman DA, Heller G, et al. Primary T cells from cutaneous T-cell lymphoma skin explants display an exhausted immune checkpoint profile. Cancer Immunol Res. (2018) 6:900–9. doi: 10.1158/2326-6066.CIR-17-0270
38. Wong HK, Wilson AJ, Gibson HM, Hafner MS, Hedgcock CJ, Berger CL, et al. Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides – cutaneous T cell lymphoma. J Invest Dermatol. (2006) 126:212–9. doi: 10.1038/sj.jid.5700029
39. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. (2016) 34:2698–704. doi: 10.1200/JCO.2015.65.9789
40. Khodadoust MS, Rook AH, Porcu P, Foss F, Moskowitz AJ, Shustov A, et al. Pembrolizumab in relapsed and refractory mycosis fungoides and Sézary syndrome: a multicenter phase II study. J Clin Oncol. (2020) 38:20–8. doi: 10.1200/JCO.19.01056
41. Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. (2018) 19:1192–204. doi: 10.1016/S1470-2045(18)30379-6
43. Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol. (1992) 99:90–4. doi: 10.1111/1523-1747.ep12611877
44. Chong BF, Wilson AJ, Gibson HM, Hafner MS, Luo Y, Hedgcock CJ, et al. Immune function abnormalities in peripheral blood mononuclear cell cytokine expression differentiates stages of cutaneous T-cell lymphoma/mycosis fungoides. Clin Cancer Res. (2008) 14:646–53. doi: 10.1158/1078-0432.CCR-07-0610
45. Kari L, Loboda A, Nebozhyn M, Rook AH, Vonderheid EC, Nichols C, et al. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med. (2003) 197:1477–88. doi: 10.1084/jem.20021726
46. Takahashi N, Sugaya M, Suga H, Oka T, Kawaguchi M, Miyagaki T, et al. Thymic stromal chemokine TSLP acts through Th2 cytokine production to induce cutaneous T-cell lymphoma. Cancer Res. (2016) 76:6241–52. doi: 10.1158/0008-5472.CAN-16-0992
47. Wolk K, Mitsui H, Witte K, Gellrich S, Gulati N, Humme D, et al. Deficient cutaneous antibacterial competence in cutaneous T-cell lymphomas: role of Th2-mediated biased Th17 function. Clin Cancer Res. (2014) 20:5507–16. doi: 10.1158/1078-0432.CCR-14-0707
48. Yoo J, Shah F, Velangi S, Stewart G, Scarisbrick JS. Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T-cell lymphoma? Clin Exp Dermatol. (2019) 44:414–7. doi: 10.1111/ced.13777
49. Berger CL, Tigelaar R, Cohen J, Mariwalla K, Trinh J, Wang N, et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood. (2005) 105:1640–7. doi: 10.1182/blood-2004-06-2181
50. Borcherding N, Voigt AP, Liu V, Link BK, Zhang W, Jabbari A. Single-cell profiling of cutaneous T-cell lymphoma reveals underlying heterogeneity associated with disease progression. Clin Cancer Res. (2019) 25:2996–3005. doi: 10.1158/1078-0432.CCR-18-3309
51. Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet. (2015) 47:1426–34. doi: 10.1038/ng.3444
52. Woollard WJ, Pullabhatla V, Lorenc A, Patel VM, Butler RM, Bayega A, et al. Candidate driver genes involved in genome maintenance and DNA repair in Sezary syndrome. Blood. (2016) 127:3387–97. doi: 10.1182/blood-2016-02-699843
53. Izykowska K, Przybylski GK, Gand C, Braun FC, Grabarczyk P, Kuss AW, et al. Genetic rearrangements result in altered gene expression and novel fusion transcripts in Sezary syndrome. Oncotarget. (2017) 8:39627–639. doi: 10.18632/oncotarget.17383
55. Chang LW, Patrone CC, Yang W, Rabionet R, Gallardo F, Espinet B, et al. An integrated data resource for genomic analysis of cutaneous T-cell lymphoma. J Invest Dermatol. (2018) 138:2681–3. doi: 10.1016/j.jid.2018.06.176
56. Gros A, Laharanne E, Vergier M, Prochazkova-Carlotti M, Pham-Ledard A, Bandres T, et al. TP53 alterations in primary and secondary Sézary syndrome: a diagnostic tool for the assessment of malignancy in patients with erythroderma. PLoS ONE. (2017) 12:e0173171. doi: 10.1371/journal.pone.0173171
57. Sors A, Jean-Louis F, Pellet C, Laroche L, Dubertret L, Courtois G, et al. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood. (2006) 107:2354–63. doi: 10.1182/blood-2005-06-2536
59. Zinzani PL, Musuraca G, Tani M, Stefoni V, Marchi E, Fina M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. (2007) 25:4293–7. doi: 10.1200/JCO.2007.11.4207
60. Sommer VH, Clemmensen OJ, Nielsen O, Wasik M, Lovato P, Brender C, et al. In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3. Leukemia. (2004) 18:1288–95. doi: 10.1038/sj.leu.2403385
61. Verma NK, Davies AM, Long A, Kelleher D, Volkov Y. STAT3 knockdown by siRNA induces apoptosis in human cutaneous T-cell lymphoma line Hut78 via downregulation of Bcl-xL. Cell Mol Biol Lett. (2010) 15:342–55. doi: 10.2478/s11658-010-0008-2
63. Park J, Yang J, Wenzel AT, Ramachandran A, Lee WJ, Daniels JC, et al. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood. (2017) 130:1430–40. doi: 10.1182/blood-2017-02-768234
64. Willerslev-Olsen A, Krejsgaard T, Lindahl LM, Litvinov IV, Fredholm S, Petersen DL, et al. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood. (2016) 127:1287–96. doi: 10.1182/blood-2015-08-662353
65. Vermeer MH, van Doorn R, Dijkman R, Mao X, Whittaker S, van Voorst Vader PC. Novel and highly recurrent chromosomal alterations in Sézary syndrome. Cancer Res. (2008) 68:2689–98. doi: 10.1158/0008-5472.CAN-07-6398
66. Laharanne E, Oumouhou N, Bonnet F, Carlotti M, Gentil C, Chevret E, et al. Genome-wide analysis of cutaneous T-cell lymphomas identifies three clinically relevant classes. J Invest Dermatol. (2010) 130:1707–18. doi: 10.1038/jid.2010.8
67. Lin WM, Lewis JM, Filler RB, Modi BG, Carlson KR, Reddy S, et al. Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients. J Invest Dermatol. (2012) 132:188–97. doi: 10.1038/jid.2011.254
70. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. (2007) 12:1247–52. doi: 10.1634/theoncologist.12-10-1247
71. Grant C, Rahman F, Piekarz R, Peer C, Frye R, Robey RW, et al. Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors. Expert Rev Anticancer Ther. (2010) 10:997–1008. doi: 10.1586/era.10.88
73. Narducci MG, Arcelli D, Picchio MC, Lazzeri C, Pagani E, Sampogna F, et al. MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome. Cell Death Dis. (2011) 2:e151. doi: 10.1038/cddis.2011.32
74. Ralfkiaer U, Hagedorn PH, Bangsgaard N, Løvendorf MB, Ahler CB, Svensson L, et al. Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL). Blood. (2011) 118:5891–900. doi: 10.1182/blood-2011-06-358382
77. Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle. (2013) 12:1939–47. doi: 10.4161/cc.24987
78. Seto AG, Beatty X, Lynch JM, Hermreck M, Tetzlaff M, Duvic M, et al. Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma. Br J Haematol. (2018) 183:428–44. doi: 10.1111/bjh.15547
79. Foss FM, Querfeld C, Kim YH, Pinter-Brown LC, William BM, Porcu P, et al. Ph 1 study of MRG-106, an inhibitor of miR-155. J Clin Oncol. (2018) 36(Suppl. 15):2511. doi: 10.1200/JCO.2018.36.15_suppl.2511
80. Lindahl LM, Besenbacher S, Rittig AH, Celis P, Willerslev-Olsen A, Gjerdrum LMR, et al. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study. Blood. (2018) 131:759–70. doi: 10.1182/blood-2017-06-788950
81. Shen X, Wang B, Li K, Wang L, Zhao X, Xue F, et al. MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma. J Invest Dermatol. (2018) 138:2024–32. doi: 10.1016/j.jid.2018.03.1500
83. Gaydosik AM, Tabib T, Geskin LJ, Bayan CA, Conway JF, Lafyatis R, et al. Single-cell lymphocyte heterogeneity in advanced cutaneous T-cell lymphoma skin tumors. Clin Cancer Res. (2019) 25:4443–54. doi: 10.1158/1078-0432.CCR-19-0148
85. Rozati S, Cheng PF, Widmer DS, Fujii K, Levesque MP, Dummer R. Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. Clin Cancer Res. (2016) 22:2020–31. doi: 10.1158/1078-0432.CCR-15-1435
86. Kim SR, Lewis JM, Cyrenne BM, Monico PF, Mirza FN, Carlson KR, et al. BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. Oncotarget. (2018) 9:29193–207. doi: 10.18632/oncotarget.25670
87. Samimi S, Morrissey K, Anshelevich S, Evans K, Gardner J, Musiek A, et al. Romidepsin and interferon gamma: a novel combination for refractory cutaneous T-cell lymphoma. J Am Acad Dermatol. (2013) 68:e5–6. doi: 10.1016/j.jaad.2011.06.043
88. Vu K, Wu CH, Yang CY, Zhan A, Cavallone E, Berry W, et al. Romidepsin plus liposomal doxorubicin is safe and effective in patients with relapsed or refractory T-cell lymphoma: results of a phase I dose-escalation study. Clin Cancer Res. (2020) 26:1000–8. doi: 10.1158/1078-0432.CCR-19-2152
89. Froehlich TC, Müller-Decker K, Braun JD, Albrecht T, Schroeder A, Gülow K, et al. Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma. Blood. (2019) 134:445–55. doi: 10.1182/blood.2019001545
90. Zhao L, Okhovat JP, Hong EK, Kim YH, Wood GS. Preclinical studies support combined inhibition of BET family proteins and histone deacetylases as epigenetic therapy for cutaneous T-cell lymphoma. Neoplasia. (2019) 21:82–92. doi: 10.1016/j.neo.2018.11.006
91. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA. (2008) 105:13520–5. doi: 10.1073/pnas.0804295105
92. Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. (2016) 540:433–37. doi: 10.1038/nature20598
94. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. (2018) 378:439–48. doi: 10.1056/NEJMoa1709866
Keywords: cutaneous T cell lymphoma (CTCL), mycosis fungoides, sezary syndrome, single cell profiling, precision medicine, next generation sequencing, tumor microenvironment
Citation: Phyo ZH, Shanbhag S and Rozati S (2020) Update on Biology of Cutaneous T-Cell Lymphoma. Front. Oncol. 10:765. doi: 10.3389/fonc.2020.00765
Received: 25 October 2019; Accepted: 21 April 2020;
Published: 12 May 2020.
Edited by:Alessandra Romano, University of Catania, Italy
Reviewed by:Robert Gniadecki, University of Alberta, Canada
Cosimo Di Raimondo, Policlinico Tor Vergata, Italy
Tanya Hundal, Mayo Clinic, United States
Copyright © 2020 Phyo, Shanbhag and Rozati. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sima Rozati, firstname.lastname@example.org