Deconvolution of Adult T-Cell Leukemia/Lymphoma With Single-Cell RNA-Seq Using Frozen Archived Skin Tissue Reveals New Subset of Cancer-Associated Fibroblast

Abstract

Adult T-cell Leukemia/Lymphoma (ATLL) is a rare aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. However, little is known about the underlying activated molecular pathways at the single cell level. Moreover, the intercellular communications between the tumor microenvironment (TME) and tumor cells in this malignancy are currently unknown. Difficulties in harvesting fresh tissue in a clinical setting have hampered our deeper understanding of this malignancy. Herein, we examined ATLL using archived fresh frozen tissue after biopsy using single-cell RNA sequencing (scRNA-seq) with T-cell receptor (TCR) clonal analysis. Highly clonal tumor cells showed multiple activating pathways, suggesting dynamic evolution of the malignancy. By dissecting diverse cell types comprising the TME, we identified a novel subset of cancer-associated fibroblast, which showed enriched epidermal growth factor receptor (EGFR)-related transcripts including early growth response 1 and 2 (EGR1 and EGR2). Cancer associated fibroblasts (CAFs) of ATLL play an important role for CD4 T-cell proliferation via FGF7-FGF1 and PDGFA-PDGFRA/B signaling, and CAFs, particularly EGR-enriched, are also associated with CD8 and NKT expansion by EGFR. These findings suggest a potential targeted therapeutic pathway to better treat this neoplasm.

Advances in single-cell RNA sequencing and its applications in cancer research

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Resistance mechanisms of immune checkpoint inhibition in lymphoma: Focusing on the tumor microenvironment

“…The difference may be related to heterogenous nature of CAFs, and further investigation of subsets is required. Recently, singled-cell sequencing has also been utilized to characterize CAFs in lymphoma, identifying a novel subgroup of CAFs characterized by high expression of EGR genes, which facilitates T and NK cell expansion via epidermal growth factor receptor ( Joo et al, 2022 ). In summary, the predictive value of CAFs in ICIs treatments remains to be elucidated in lymphoma.…”

Cancer-associated fibroblasts in hematologic malignancies: elucidating roles and spotlighting therapeutic targets

“…( 47 ). Additionally, CAF/EGR high influences CD8 and NKT cell expansion through EGFR ( 47 ). These findings suggest potential avenues for targeted therapy.…”