Cellular and molecular profiling of lymphomatoid papulosis reveals factors associated with indolent vs. aggressive CTCL behavior

Summary: Abstract Body: Primary cutaneous T-cell lymphomas (CTCL) comprise a diverse spectrum of neoplastic skin conditions, ranging from self-limiting CD30+ lymphoproliferative disorders such as lymphomatoid papulosis (LyP) to aggressive systemic CTCL. However, mechanisms underlying their specific clinical disease behavior are insufficiently understood. Using single-cell RNA sequencing combined with T cell receptor sequencing, we conducted molecular profiling of skin biopsies from LyP that harbored either a CD4+, CD8+ or TCR-γδ+ clonal phenotype, and compared results to cases of advanced-stage CTCL (CD4+ mycosis fungoides, aggressive epidermotropic CD8+ cytotoxic lymphoma, and TCR-γδ+ mycosis fungoides) with a subsequently lethal disease outcome. Expanded clones of LyP harbored an overall GZMA+GNLY+PRF1+ cytotoxic-like immune phenotype. Importantly, this signature was independent of their CD4, CD8 or TCR-γδ lineage. Advanced-stage CTCL lesions of all subsets, by contrast, showed a transcriptomic pattern that was more reminiscent of helper T cells, but showed a high degree of heterogeneity. Nevertheless, we found that advanced-stage CTCL tumor clones were distinguished by uniform expression of a characteristic panel of 8 genes (LTB, IL32, ISG15, GIMAP5, GIMAP7, MT2A, BATF and SNHG8) across CD4, CD8 and TCR-γδ clones. Within the tumor microenvironment, we detected a unique population of SPP1+ LyP-specific macrophages expressing the M1-associated markers INHBA, IL1B, and FBP1, in line with the more cytotoxic / type-1 associated immune microenvironment in LyP, that was largely absent in all subsets of advanced-stage CTCL. Taken together, we found immune mediators associated with indolent vs. aggressive clinical disease behavior, which might be relevant for future immunomodulatory treatment strategies in CTCL. Sumanth Chennareddy¹, Katharina Rindler², Natalia Alkon², Emry R. Cohenour¹, Shannon Meledathu¹, Malini Naidu¹, Lauren R. Port¹, Agata Kurowski¹, Constanze Jonak², Patrick M. Brunner¹ 1. Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. Medizinische Universitat Wien, Vienna, Vienna, Austria. UV Biology/Injury and Non-melanoma Cancers