Integrated transcriptome and trajectory analysis of cutaneous T-cell lymphoma identifies putative precancer populations

Abstract

Cutaneous T-cell lymphoma (CTCL) incidence increases with age, and blood involvement portends a worse prognosis. To advance our understanding of CTCL development and identify potential therapeutic targets, we performed integrative analyses of paired single-cell RNA and TCR sequencing of peripheral blood CD4+ T-cells from CTCL patients to reveal disease unifying features. The malignant CD4+ T-cells of CTCL show highly diverse transcriptomic profiles across patients, with most displaying a mature Th2 differentiation and T-cell exhaustion phenotype. TCR-CDR3 peptide prediction analysis suggested limited diversity between CTCL samples, consistent with a role for a common antigenic stimulus. PHATE affinity-based transition analysis identified putative precancerous circulating populations characterized by an intermediate stage of gene expression and mutation level between the normal CD4+ T-cells and malignant CTCL cells. We further revealed the therapeutic potential of targeting CD82 and JAK that endow the malignant CTCL cells with survival and proliferation advantages.

Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma

“…Large inter-patient gene expression heterogeneity in the malignant T-cell population was additionally observed in fresh skin biopsies derived from eight patients with tCTCL in the study by Song et al [ 70 ]. In agreement with the previous report [ 73 ], this contrasted the more preserved gene expression profile observed in the normal T cell counterparts across patients. Significant enrichment of genes involved in the oxidative phosphorylation (OXPHOS), MYC, cellular plasticity, and stemness signaling pathways was shown in the malignant T-cell population derived from the transformed tumor (TT) lesions.…”

“…Using paired scRNA and TCR sequencing, inter-patient heterogeneity at the transcriptional level was demonstrated by Ren et al in the blood-circulating malignant T-cell population, whereas substantial similarities were shared among the normal T cell counterparts across 11 patients [ 73 ]. Application of the potential of heat diffusion for affinity-based trajectory embedding (PHATE) analysis showed the presence of a pre-cancerous population featured by an intermediate phenotype at the transcriptional and genetic mutational level when compared to normal T cells and clonal CTCL cells.…”

“…In agreement with previous reports, within the malignant T-cell population among the most enriched pathways in the malignant T cells were the TCR and JAK/STAT signaling pathways. Several exhaustion markers, including TOX , TIGIT , LAG3 , CTLA4 , and PDCD1 were significantly increased in the clonal malignant T-cell population, prompting the authors to propose that malignant CTCL cells might acquire an exhausted phenotype due to chronic antigenic stimulation during CTCL development [ 73 ]. For example, the CD82 molecule that encodes a cell surface protein marker found upstream of JAK/STAT and AKT/PI3K pathways was identified and suggested as a novel therapeutic target for CTCL patients.…”

“…For example, the CD82 molecule that encodes a cell surface protein marker found upstream of JAK/STAT and AKT/PI3K pathways was identified and suggested as a novel therapeutic target for CTCL patients. It was shown that JAK-inhibitors play a potential therapeutic role via reducing CD82-dependent malignant T cell proliferation and survival ex vivo [ 73 ].…”

Multiomic Data Integration Reveals Microbial Drivers of Aetiopathogenesis in Mycosis Fungoides

“…However, others suggest that the initial oncologic transformation takes place during early thymopoiesis, specifically during the stages double-negative (DN) DN-1 through DN-3. Those “premalignant clones” may then migrate to the skin where they proliferate ( 10–15 ). The causative agent responsible for the oncogenic transformation of T cells in MF remains uncertain ( 1 ).…”