Characterizing malignant T cells in CTCL to inform personalized therapy: A scRNAseq study

Summary: Abstract Body: Single-cell RNA sequencing (scRNAseq) provides novel insights into cancer biology and cellular interactions, yet its application to cutaneous T-cell lymphoma (CTCL) remains limited. CTCL’s overlap between malignant and benign T cells requires strategies to identify and target malignant populations. We analyzed 105,806 PBMCs from 23 CTCL patients with blood involvement (9 UT Southwestern and 14 publicly available) and identified four malignant T-cell phenotypes: central memory/naïve (MTC CM/N), effector memory (MTC EM), regulatory (MTC Reg), and cytotoxic effector memory (MTC CyEM). Malignant cells were defined using transcriptomic, TCR sequencing, and CNV analyses, with benign T-cells as references. Key gene signatures characterized each phenotype. MTC CM/N, the largest subset, upregulated KIR3DL2 (log2FC 1.95), NEDD4L (2.02), and IGFBP4 (1.94), while downregulating FOXP1 (-1.06). MTC EM expressed KIR3DL1 (2.13) and NR4A1 (2.50). HACD1 was shared between MTC CM/N (2.24) and MTC EM (2.10), while EGR1 characterized both MTC EM (2.10) and MTC CyEM (2.49). MTC Reg expressed HMOX1 (2.58) and TWIST1 (2.61), and MTC CyEM expressed FOSB (2.00) and TNF (1.96). Gene set enrichment analysis (GSEA) revealed functional distinctions. MTC CM/N resembled benign T CM/N but with reduced cytoplasmic translation (NES -2.00, FDR 0.07). MTC EM displayed metabolic shifts with decreased oxidative phosphorylation (NES < -1.5, FDR < 0.05). MTC Reg had reduced apoptotic signaling (NES -1.97, FDR < 0.05) and heightened hypoxia responses (NES 1.89, FDR < 0.05). MTC CyEM had inflammatory signatures (NES 2.19, FDR < 0.05) and reduced cellular respiration (NES -1.71, FDR < 0.05). These findings highlight CTCL’s malignant T-cell diversity and support personalized therapies. High KIR3DL2 in MTC CM/N supports lacutamab trials, while metabolic and inflammatory pathways in other phenotypes suggest therapeutic targets. Investigation of cell types in the tumor environment is ongoing. Beth A. Childs¹, Eslam Elghonaimy², Todd Aguilera², Heather W. Goff¹ 1. Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 2. The University of Texas Southwestern Medical Center Department of Radiation Oncology, Dallas, TX, United States. UV Biology/Injury and Non-melanoma Cancers