Cutaneous T-cell lymphoma is a rare cancer of skin-homing T-cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole exome sequencing (WES), single-cell RNA-seq and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation, cellular plasticity, upregulation of MYC and E2F activities and down-regulation of MHC-I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent anti-tumor activities, while immune profiling provided in situ evidence of intercellular communications between malignant T-cells expressing macrophage migration inhibitory factor and macrophages and B-cells expressing CD74.

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