The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome.

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment.

The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication.

Cutaneous T cell lymphomas (CTCLs) are malignancies of skin-trafficking T cells. Patients with advanced CTCL manifest immune dysfunction that predisposes to infection and suppresses the antitumor immune response. Therapies that stimulate immunity have produced superior progression-free survival compared with conventional chemotherapy, reinforcing the importance of addressing the immune deficient state in the care of patients with CTCL. Recent research has better defined the pathogenesis of these immune deficits, explaining the mechanisms of disease progression and revealing potential therapeutic targets. The features of the malignant cell in mycosis fungoides and Sézary syndrome are now significantly better understood, including the T helper 2 cell phenotype, regulatory T cell cytokine production, immune checkpoint molecule expression, chemokine receptors, and interactions with the microenvironment. The updated model of CTCL immunopathogenesis provides understanding into clinical progression and therapeutic response.

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40-OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40-OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.

Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous disease group of unknown etiology with a complex immunological background. As CTCL arises from T cells that have a vital role in the antitumor response, their therapy is largely aimed at reversing the immunological mechanisms leading to or manifesting during this malignancy. Early disease stages can be controlled with skin-directed therapy in most CTCL cases. Still, advanced CTCL has a dismal prognosis and warrants systemic therapy. Despite considerable progress in understanding the pathophysiology of the disease and the numerous systemic treatment options available, long-term remission rates with conventional treatments alone are still low. Allogeneic hematopoietic stem cell transplantation is currently the only curative option for advanced CTCL, including mycosis fungoides and Sézary syndrome. The aims of this review is to summarize the recent findings on the immunology of this heterogeneous disease and to present the advances in its clinical management.

A Long-Term Study of Persistent Sézary Syndrome: Evidence for Antigen Shift by Multiparameter Flow Cytometry and Its Significance in Overall Survival.

Sézary syndrome (SS) is a peripheral T-cell lymphoma characterized by erythroderma, diffuse lymphadenopathy, and circulating neoplastic T cells, which classically show a helper T-cell immunophenotype with loss of CD7 and CD26. Flow cytometry is often used to identify and enumerate populations of Sézary cells in the peripheral blood; however, the significance and frequency of antigen shift over time is unclear. In this article, we follow the immunophenotype of the neoplastic T-cell population from 28 patients with SS across 415 flow cytometry studies. Antigen shift for each patient was assigned as none, minimal = 1-2 markers by 1°, moderate = up to 3 markers, or marked ≥ 4 markers. Sixty-four percent (18/28) of patients showed antigen shift, and among those with antigen shift, the majority showed minimal (8/18) or moderate antigen shift (7/18) with fewer demonstrating marked shift (3/18). Patients without antigen shift showed a trend toward improved overall survival in comparison with patients demonstrating any degree of antigen shift. Antigen shift is seen in a significant proportion of cases of SS with long-term follow-up and may be a marker of more aggressive disease.

A histo-immunopathologic and prognostic study of erythrodermic cutaneous T-cell lymphoma.

BACKGROUND: Sézary syndrome (SS) and erythrodermic mycosis fungoides (E-MF) represent two expressions of erythrodermic cutaneous T-cell lymphoma (E-CTCL). METHODS: Histopathologic features were compared on skin specimens from 41 patients with SS and 70 patients with E-MF. Immunopathologic findings were compared on 42 SS and 79 E-MF specimens. RESULTS: Specimens of SS usually showed band-like dermal infiltrates with intermediate-sized lymphoid cells and few plasma cells; on the other hand E-MF more often had a perivascular infiltrative pattern, predominance of small/mixed lymphoid cells and eosinophils. SS also had lower numbers of CD8+ cells and higher numbers of CD62L+ cells compared to E-MF. For E-MF patients, the presence of large Pautrier collections, infiltrates with intermediate-sized cells, increased number of mitotic figures and ≥50% CD62L+ cells in the dermal infiltrate correlated with a relatively poor disease-specific survival. However, only the presence of mitotic figures retained prognostic significance with clinical stage as a covariate. CONCLUSIONS: Clinical stage provides the most important prognostic information for patients with E-CTCL. However, mitotic activity for E-MF and CD8+ cells <20% for SS have additional value. We hypothesize that observed differences in plasma cell and eosinophil numbers may reflect the influence of CD62L+ central memory T-cells in the microenvironment.

Expression of CCR3 and CCR4 Suggests a Poor Prognosis in Mycosis Fungoides and Sézary Syndrome.

Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, lym-phomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30+ lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30+ lym-phoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.

Immunotherapy for Cutaneous T-Cell Lymphoma: Current Landscape and Future Developments.

Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic, progressive primary cutaneous T-cell lymphomas (CTCLs) for which there are no curative treatments. Skin-directed therapies, such as phototherapy, radiation therapy, or topical nitrogen mustard, provide only short-term remissions. Numerous attempts with different chemotherapeutic regimes failed to achieve meaningful clinical responses. Immunotherapy seems to be a promising avenue to achieve long-term disease control in CTCL. There is compelling evidence indicating that MF and SS are immunogenic lymphomas, which can be recognized by the patient's immune system. However, CTCL uses different strategies to impair host's immunity, eg, via repolarizing the T-cell differentiation from type I to type II, recruiting immunosuppressive regulatory T-cells, and limiting the repertoire of lymphocytes in the circulation. Many currently used therapies, such as interferon-α, imiquimod, extracorporeal phototherapy, and allogeneic bone marrow transplant, seem to exert their therapeutic effect via activation of the antitumor cytotoxic response and reconstitution of the host's immune system. It is likely that novel immunotherapies such as immune checkpoint inhibitors, cancer vaccines, and chimeric antigen receptor-T cells will help to manage CTCL more efficiently. We also discuss how current genomic techniques, such as estimating the mutational load by whole genome sequencing and neoantigen calling, are likely to provide clinically useful information facilitating personalized immunotherapy of CTCL.

Rapid progression of immune dysregulation in an HIV-infected patient with Sézary syndrome.

A 44-year-old man known to have human immunodeficiency virus (HIV) infection presented to our clinic with erythroderma, generalized lymphadenopathy, and cutaneous nodules and tumors. After a series of investigations, we confirmed that he had Sézary syndrome. In this paper we describe the immune alterations that occur in both Sézary Syndrome and HIV infection and how these changes together resulted in rapid and overwhelming immune dysregulation in our patient.

Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome.

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4+CD25- responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

Molecular pathogenesis of cutaneous lymphomas.

Primary cutaneous T-cell lymphoma (CTCL) comprises the second most common group of extra-nodal non-Hodgkin's lymphoma. They represent incurable primary extra-nodal lymphomas of major T cells, uniformly present in the skin with 1%-2% risk of systemic dissemination in mycosis fungoides (MF), which represents the most common subtype of CTCL. In general, long-term antigen stimulation is thought, through key cytokine signalling pathways, to induce an inflammatory response with T-cell proliferation, leading to a clonal malignant T cell with continuous expansion. However, in recent years, using data harvested from high-throughput transcriptional profiling, substantial advances in the understanding of the molecular pathogenesis were made to understand the complex pathogenesis of CTCL. In this review, the actual data are summarised.

Infectious events and associated risk factors in mycosis fungoides/Sézary syndrome: a retrospective cohort study.

BACKGROUND: Infections are one of the major causes of death in patients with advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS). However, few recent data are available on the characteristics and risk factors of these infectious events. OBJECTIVES: To describe infectious events occurring in a cohort of patients with MF/SS, and to identify associated clinical and biological risk factors. METHODS: A retrospective cohort study was performed to investigate infectious events and associated factors in patients diagnosed with MF (stage IB and beyond) or SS followed from May 2011 to May 2016 at the University Hospital of Bordeaux, France. RESULTS: Seventy-one patients with complete follow-up were included. Eighty infectious events were recorded in 40 patients, including 28 skin and soft tissue infections and 25 cases of pneumonia. Opportunistic infections, which are usually associated with depleted cell-mediated immunity, were scarce (9%). In multivariate analysis, cardiac, renal or lung comorbidities [odds ratio (OR) 7·2, 95% confidence interval (CI) 3·3-15·9; P = 0·002], SS (OR 8·8, 95% CI 7·7-10·2; P = 0·037) and lymphocyte count < 0·5 × 109 cells L-1 (OR 6·4, 95% CI 1·5-27·4; P = 0·004) were significantly associated with a higher risk of infection. CONCLUSIONS: Opportunistic germs were rarely recorded, but their incidence was probably prevented by adequate prophylaxis (ongoing in 28% of patients). As in patients living with AIDS, pneumonias were frequent. On the other hand, bacterial cutaneous infections represent a specific pattern in patients with MF/SS. Patients with chronic organ failure, lymphocytopenia and SS should be considered as being at high risk for infectious events. Pneumococcal vaccination should be systematically recommended, and prophylaxis with co-trimoxazole and valaciclovir when the CD4 count is < 0·2 × 109 cells L-1 .

Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome.

A phase 2 multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of 6 prior treatment regimens, including a median of 4 systemic therapies. Patients achieved an overall response rate of 28% (9 patients), and all were partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25-mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain, and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25(+) T cells and CD4(+) T-cell numbers. Skin lesions showed a trend for increased CD8, CD25, and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory cutaneous T-cell lymphomas, along with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT00466921.

Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors before escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Reflectance confocal microscopy features of mycosis fungoides and Sézary syndrome: correlation with histopathologic and T-cell receptor rearrangement studies.

BACKGROUND: Mycosis fungoides/Sézary syndrome (MF/SS) often requires multiple skin biopsies for definitive diagnosis. In vivo reflectance confocal microscopy (RCM) visualizes high-resolution cellular detail of the skin. The objective of this study is to evaluate the morphologic features of MF/SS using RCM and to correlate RCM features with histopathology and T-cell receptor (TCR) gene rearrangement studies. METHODS: A cohort of patients with active/recurrent or suspicious MF/SS disease was prospectively recruited for RCM imaging and histopathologic/RCM images were evaluated. Statistical analyses were performed to identify unique RCM features and to correlate RCM features with histopathologic findings and TCR rearrangement studies. RESULTS: Eighty-three lesions were evaluated. Correlation between RCM and histopathology was moderate for all relatable features (κ = 0.41, p<0.001), almost perfect for intraepidermal atypical lymphocytes [prevalence and bias-adjusted kappa (PABAK) = 0.90], and fair for Pautrier collections (κ = 0.32, p = 0.03). Lesions with Pautrier collections identified by RCM were significantly more likely to show TCR clonality (p = 0.04) and diagnostic features of MF/SS on histopathology (p = 0.03). CONCLUSIONS: Our study captures morphologic RCM criteria for a variety of skin lesions. Pautrier collections visualized by RCM are associated with improved histopathologic diagnosis and detection of TCR gene clonality. Although further studies are needed to validate the diagnostic implications of RCM for MF/SS, our study highlights the potential utility of RCM.

Expression of CD164 on Malignant T cells in Sézary Syndrome.

Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sézary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sézary syndrome specific cell surface marker has been identified. In a cohort of patients with Sézary syndrome, CD164 expression on total CD4+ lymphocytes was significantly upregulated compared with healthy controls. CD164 expression was in most cases limited to CD4+CD26- malignant T lymphocytes, unequivocally identified using flow-cytometry by the expression of a specific Vß clone for each patient. Increased expression of CD164 may be a promising diagnostic parameter and a potential target for a CD164-linked therapeutic approach in Sézary syndrome.

Sézary syndrome: old enigmas, new targets.

Sézary syndrome, the leukemic variant of cutaneous T-cell lymphoma, is still an enigmatic disease with a fatal prognosis. Recent research, however, has identified a multitude of dysregulated molecular pathways that contribute to malignant transformation and therapy resistance of Sézary cells (SC). With respect to T-cell development, SC either represent naive T cells, T effector memory or T central memory cells. Functionally, SC may differentiate into Th2, Treg, or even Th17 cells. Despite their plasticity, SC express characteristic diagnostic marker proteins including CD158k, CD164, FcRL3, and PD-1 as well as skin-homing receptors such as CLA and CCR4. Already tested in (pre)clinical trials, CD158k, PD-1, CTLA-4, and CCR4 also represent promising therapeutic targets. Molecular alterations in SC include transcription factors such as STAT3, 4, and 5, as well as TWIST1 and TOX. TWIST1 induces expression of DNM3os containing the miR-199a2/214 cluster, a key hub controlling multiple cancer networks. In addition, activation of NFκB and the MAPK pathway as well as altered TCR signaling cause apoptosis resistance. Recently, whole genome and exome sequencing has revealed somatic copy number variations as predominant mutations in SC, primarily affecting apoptosis, NFκB signaling, DNA integrity, and T-cell activation. In order to facilitate development of novel therapies, improved in vivo models, which better reflect the pathogenesis and clinical course of Sézary syndrome, are currently being generated.

Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases.

BACKGROUND: Patients with erythrodermic disease are a diagnostic challenge regarding the clinical and histological differential diagnosis. OBJECTIVES: To evaluate histopathological and immunohistochemical diagnostic markers for Sézary syndrome. METHODS: Ninety-seven erythrodermic cases [Sézary syndrome (SS), n = 57; erythrodermic inflammatory dermatoses (EIDs), n = 40] were collected by the EORTC Cutaneous Lymphoma Task Force histopathology group. Evaluation criteria were (i) epidermal and dermal changes; (ii) morphology of the infiltrate; (iii) immunohistochemical analysis of marker loss (CD2, CD3, CD4, CD5 and CD7); (iv) bystander infiltrate by staining for CD8, FOXP3 and CD25; and (v) expression of Ki-67, CD30, PD-1 and MUM-1. RESULTS: The workshop panel made a correct diagnosis of SS in 51% of cases (cutaneous T-cell lymphoma 81%) and of EID in 80% without clinical or laboratory data. Histology revealed a significantly increased degree of epidermotropism (P < 0.001) and more intraepidermal atypical lymphocytes (P = 0.0014) in SS biopsies compared with EID. Pautrier microabscesses were seen only in SS (23%) and not in EID (P = 0.0012). SS showed significantly more dermal cerebriform and blastic lymphocytes than EID. Immunohistochemistry revealed a significant loss of CD7 expression (< 50%) in 33 of 51 (65%) cases of SS compared with two of 35 (6%) EID (P < 0.001). The lymphocytic infiltrate in SS skin samples was found significantly to express PD-1 (P = 0.0053), MUM-1 (P = 0.0017) and Ki-67 (P < 0.001), and showed less infiltration of CD8(+) lymphocytes (P < 0.001). A multivariate analysis identified CD7 loss, increased numbers of small cerebriform lymphocytes, low numbers of CD8(+) lymphocytes and increased proliferation (Ki-67(+) lymphocytes) as the strongest indicators for the diagnosis of SS. CONCLUSIONS: A number of different histological and immunophenotypical criteria are required to differentiate between SS and EIDs.