118 Single-cell transcriptomics links cellular origins of malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma

Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis, paired V(D)J sequencing and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we deciphered the intra-tumor and inter-lesion diversity of CTCL patients and proposed a multi-step tumor evolution model. The activation/proliferation status of malignant T cells determined the heterogeneity of CTCL lesions, which was found to be related to patient prognosis. We identified the mono-clonal nature of malignant T cells and proposed a model of a multi-step subclonal evolutionary process, deciphering the inter-lesion diversity of CTCL patients. We further established a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the TCyEM group, demonstrating a cytotoxic effector memory T cell phenotype, showed more M2 macrophages infiltration, while the TCM group, featured by a central memory T cell phenotype and adverse patient outcome, was infiltrated by highly exhausted CD8+ reactive T cells, B cells and Tregs with suppressive activities. Distinct molecular signatures, clinical behaviors, and tumor microenvironments were identified in the two groups. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.