The difficulty in distinguishing malignant T cells from reactive T cells presents an obstacle to understand the immune landscape of the tumor microenvironment (TME) in CTCL. However, the molecular mechanisms underlying this inter-lesional diversity remain to be defined. Moreover, CTCL patients frequently show inter-lesional diversity in treatment responses, adding to the complexity of the clinical challenge of the disease and often creating obstacles to achieving effective therapy 9.
#Cutaneous tcel lymphoma skin
CTCL generally exhibits an indolent course, but a portion of patients progresses rapidly and exhibit widespread disease beyond the skin despite aggressive treatment, highlighting the underlying heterogeneity of this disease. Owing to the poor understanding of disease pathogenesis, effective treatments for CTCL are limited, and the treatment response varies greatly among patients. This discrepancy is largely due to the difficulty in discriminating true malignant T cells from benign reactive T cells in CTCL skin lesions, since there are no specific markers to define malignant T cells, which also results in delayed diagnosis and poor prognosis for CTCLs. However, recent evidence indicates that malignant T cells are derived from circulating immature precursor cells, which seed the skin and evolve into clonally heterogeneous lymphomas 6, 7, 8. Previous studies suggested that neoplastic T cells in CTCL originated from mature, monoclonal, skin-resident memory T cells 5. Unlike solid tumors, CTCL starts with multi-focal skin lesions, which leads to controversies regarding the tumor origin and evolution pattern of CTCL. Given the numerous shared and disparate properties of CTCL variants, it remains unclear whether these entities are distinct disorders or a continuum with a degree of genetic diversity and varied microenvironments.ĭespite tremendous progression in the understanding of CTCL in recent decades, the origin and nature of malignant T cells remain to be defined. These entities frequently coexist in the same patient, whether they develop simultaneously or as a secondary lymphoma 4. These three CTCL variants are highly related and have overlapping clinical and immunophenotypic features 2, 3. Sézary syndrome, the leukemic form of CTCL, is characterized by generalized skin erythema with leukemic malignant T cells in the blood, while pcALCL is characterized by single or multiple skin tumors and a tendency for systemic involvement in the late stage. MF begins with multiple patches, plaques and tumors in the skin, and it may involve lymph nodes, peripheral blood and viscera in the advanced stage, leading to a poor prognosis 1. Mycosis fungoides (MF), Sézary syndrome and primary cutaneous anaplastic large cell lymphoma (pcALCL) constitute the majority of CTCLs and are believed to be derived from skin-homing mature T cells. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.Ĭutaneous T cell lymphomas (CTCL) is a heterogeneous group of extranodal non-Hodgkin’s lymphomas characterized by cutaneous infiltration of clonal malignant T cells. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the T CyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the T CM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8 + reactive T cells, B cells and Tregs with suppressive activities. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. Nature Communications volume 13, Article number: 1158 ( 2022)Ĭutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells.
Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
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