A single-cell atlas identifies oncogenic transcriptional programs and immune escape mechanisms in CTCL.

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas. Outcomes for patients with advanced-stage disease are suboptimal, because few complete and durable responses are achieved with currently available therapeutic agents. However, improved understanding of oncogenic transcriptional programs in malignant T cells and their engagement with the tumor microenvironment (TME) may unveil therapeutic vulnerabilities. Therefore, we have compiled the largest available single-cell RNA-sequencing CTCL atlas that includes >2 million skin and blood cells from 116 individual patients. We identified recurrent transcriptional programs in malignant T cells, a subset of which are associated with GATA binding protein 3-dependent transcriptional programs, especially in the setting of large cell transformation and advanced-stage disease. Many of the transcriptional programs identified are therapeutically targetable with clinically available agents, including HDAC, XPO1, CDK9, JAK/CSF1R, and IKZF1/IKZF3 antagonists. The CTCL TME is dominated by infiltrating and exhausted effector and cytotoxic T cells that are restrained by a robust infiltrate of regulatory T cells, transcriptionally polarized monocytes/macrophages, and cancer-associated fibroblasts. Collectively, these findings have significant implications for the rational design of combinatorial strategies targeting immune checkpoints, including programmed cell death protein 1. We have identified transcriptional programs, driven by oncogenic transcription factors, and constituents of the TME as therapeutic vulnerabilities in CTCL, and hope that the CTCL atlas constructed will provide a valuable resource for future studies exploiting these therapeutic vulnerabilities.