Role of aberrant genetic events and skin pathobionts in CTCL

Multimodal single-cell analysis and a mouse model of cutaneous T-cell lymphoma (CTCL) suggest that aberrant genetic events (mutations and translocations) are critical to transforming T-lymphocytes. Other triggers like skin pathobionts, most notably S. Aureus, also contribute to disease progression.

Little is known about what triggers the initiation and progression of CTCL. Dr Sergej Kovalov (NYU School of Medicine, NY, US) and colleagues performed 2 research techniques to explore this issue [1]. They used multimodal single-cell analysis (expanded cellular indexing of transcriptomes and epitomes by sequencing: ExCITE-seq) to examine gene expression, surface phenotype, and clonality of circulating malignant cells and skin tumour microenvironment in advanced mycosis fungoides and Sézary syndrome. They also evaluated the role of microbial triggers and skin irritation in CTCL initiation and progression, using a novel, genetically engineered mouse model of CTCL.

Transcriptional subclustering of malignant T-cells revealed a dramatic heterogeneity. Within the reclustered malignant population, clonal evolution was tracked based on copy number variation inferal. Skin microenvironment in CTCL promoted a distinct signature within skin resident tumour cells that supported rapid proliferation and evolution of the malignant clone.

Morbidity in CTLC patients is largely due to bacterial infections; S. Aureus can potentiate clonal evolution and response to therapies. The researchers found that S. Aureus on CTLC skin is highly diverse, with super antigen and toxin production varying between the clonal clusters. Preliminary results of S. Aureus colonisation of a genetically engineered mouse model confirmed that skin pathobionts promote disease progression, as did other irritants.

1. Gumina M, et al. Clonal evolution, antigens, and triggers in cutaneous T Cell lymphoma pathogenesis. Abstract A-226, EORTC-CLTG 2024, 9-11 October 2024, Lausanne, Switserland.

Posted on 14 October 202414 October 2024