Advanced-stage cutaneous T-cell lymphomas show distinct immune profiles in erythroderma vs. tumor lesions.

Abstract

Background: Advanced-stage cutaneous T-cell lymphomas (CTCL) typically manifest as either skin tumor formation or erythroderma; however, exact mechanisms of lesion formation remain insufficiently characterized.

Objective: To better understand mechanisms of erythroderma vs. tumor formation in advanced-stage CTCL.

Methods: We compared molecular profiles of eight erythrodermic CTCL (eCTCL) with seven tumor-stage mycosis fungoides (tMF) samples by using single-cell RNA sequencing combined with T-cell receptor sequencing, and corroborated key findings using spatial transcriptomics.

Results: All samples harbored a single expanded CD4+ T-cell clone expressing TOX, IL2RG, CD27, and TCF7. While advanced-stage CTCL is generally considered a type 2-skewed disease, tMF lesions demonstrated a significantly stronger Th2/Tc2 bias than eCTCL, as evidenced by enhanced expression of CCL17 and CCL13 in myeloid cells. By contrast, eCTCL lesions displayed upregulation of several type 1-associated markers such as CXCL9. Overall, we detected considerable inter-patient heterogeneity within skin biopsies, particularly in tMF. Nonetheless, tMF consistently harbored CCL19+FDCSP+ fibroblasts and IL32+CD69+ activated B cells, phenotypes previously reported in tertiary lymphoid structure formation, alongside upregulation of multiple markers associated with vascular remodeling, angiogenesis, and extracellular matrix deposition by endothelial cells. Conversely, eCTCL exhibited higher degrees of epidermal activation and markers of anti-angiogenesis such as CXCL14 within stromal cells, which may actively counteract the development of a vertical growth phase.

Conclusion: Taken together, these data provide novel insights into the pathogenesis of advanced-stage CTCL skin lesions and potential therapeutic targets.