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

Summary: Abstract Body: Advanced-stage cutaneous T-cell lymphoma (CTCL) is defined by either skin tumor formation or erythroderma. Erythroderma is clinically defined by diffuse erythema covering >80% of the body surface area, whereas tumors are defined by vertical growth. Previous studies attribute erythroderma with the acquisition of a central memory phenotype by malignant T cells, but underlying mechanisms remain unclear. We used single-cell RNA sequencing of skin biopsies from 8 erythrodermic CTCL (eCTCL) vs. 7 tumor-stage MF (tMF) samples. Both eCTCL and tMF lesions displayed massive expansion of a single CD4+ T-cell clone expressing shared disease markers, including TOX, IL2RG, and CD27. All malignant clones expressed tissue-residency markers such as CD69, CXCR4, RGS1, and NR4A1, but at reduced levels in eCTCL, corresponding with their increased migratory potential. Thus, eCTCL clones exhibit features of central memory T cells while retaining tissue residency markers, underscoring their overall functional versatility. While advanced-stage CTCL is generally considered a type 2-skewed disease, tMF lesions demonstrated a significantly stronger Th2/Tc2 bias in our dataset, as evidenced by the overexpression of CCL17 and CCL13 in myeloid cells. In contrast, eCTCL lesions displayed a more type 1-associated immune profile with upregulation of CXCL9. Interestingly, malignant T-cell clones in tMF lesions exhibited a higher degree of inter-patient transcriptomic heterogeneity compared to the more homogeneous profiles in eCTCL. Trajectory analyses revealed distinct transcriptomic states across both eCTCL and tMF, though tMF clones uniquely occupied a CCR6+CD69+RGS1+ branch that was absent in eCTCL. Taken together, these findings reveal key molecular differences between eCTCL and tMF lesions, providing a foundation for future targeted treatment approaches. Emry Cohenour¹, Sumanth Chennareddy¹, Natalia Alkon², Lauren R. Port¹, Shannon Meledathu¹, Malini Naidu¹, Agata Kurowski¹, Constanze Jonak², Patrick M. Brunner¹ 1. Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. Dermatology, Medizinische Universitat Wien, Vienna, Vienna, Austria. Bioinformatics, Computational Biology, and Imaging