Update on Biology of Cutaneous T-Cell Lymphoma

Abstract

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.

Cellular Interactions and Inflammation in the Pathogenesis of Cutaneous T-Cell Lymphoma

“…Yet, as highlighted by recent single-cell RNA sequencing studies the malignant T cells display substantial inter- and intra-patient phenotypic heterogeneity ( Buus et al, 2018 ; Gaydosik et al, 2019 ). Extensive inter-patient heterogeneity is also observed at the genetic level and based on current data the disease is generally not caused by a few specific recurrent genetic aberrations ( Choi et al, 2015 ; da Silva Almeida et al, 2015 ; Kiel et al, 2015 ; McGirt et al, 2015 ; Ungewickell et al, 2015 ; Wang et al, 2015 ; Woollard et al, 2016 ; Iyer et al, 2020 ; Phyo et al, 2020 ). Moreover, a nationwide study of Danish twins did not detect any familial aggregation of CTCL, arguing against heredity as a dominant etiologic factor ( Odum et al, 2017 ).…”

“…Somatic genetic alterations are, however, frequently observed in genes involved in certain cellular processes and signaling pathways. In particular, genes involved in epigenetic regulation, DNA damage response, cell cycle control and programmed cell death as well as in the T cell receptor (TCR), nuclear factor-kappa B (NF-κB) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways ( Choi et al, 2015 ; da Silva Almeida et al, 2015 ; Kiel et al, 2015 ; McGirt et al, 2015 ; Ungewickell et al, 2015 ; Wang et al, 2015 ; Woollard et al, 2016 ; Iyer et al, 2020 ; Phyo et al, 2020 ). Importantly, extensive experimental data from cell lines, primary cells and clinical samples corroborate that dysregulation of these cellular processes and signaling pathways plays a central functional role in the pathogenesis of CTCL.…”

Single-Cell RNA Sequencing Reveals Tissue Compartment-Specific Plasticity of Mycosis Fungoides Tumor Cells

“…Activated CD8 + cytotoxic T-cells have been postulated as major anti-CTCL cells in early lesions when the disease is still confined to the skin, but lose this capacity when the disease progresses ( 6 ). CD8A + cells in cluster TC-5 were rich in the killer molecules GZMA ( Figure 4C ), GZMK, GZMH , and GZMB ( Figure S1 ), and were main producers of IFNG in skin and lymph nodes ( Figure 4D and Table S2 ), the type-1 lead cytokine associated with anti-CTCL properties ( 37 ). However, CD8A + cells also ubiquitously showed highest levels of CCL5 (RANTES) ( Figure 4F and Table S2 ), a chemokine previously shown to maintain CD4 + T RM cells after infection or sensitization ( 38 ), but that also attracts monocytes which were shown to promote the survival of MF cells in a mouse model ( 39 ).…”

SnapshotDx Quiz: December 2020

“…Mycosis fungoides (MF) is the most common form of CTCL, accounting for 55% of the cases (Trautinger et al, 2017). The incidence of CTCL is approximately 6.4 per million persons, with improvements in diagnosis likely accounting for reports of increased incidence (Phyo et al, 2020). Many clinical and histopathologic features of MF are nonspecific, resulting in a median time from onset of symptoms to diagnosis of between 3 and 4 years.…”