Single-cell sequencing uncovers clonal dynamics profiles and therapeutic resistance biomarkers in relapsed and refractory peripheral T-cell lymphoma.

Authors

Ning Zhang, Jingwei Yu, Hengqi Liu, Zechao Hu, Shen Meng, Cong Sun, Yaxiao Lu, Xia Liu, Zheng Song, Lanfang Li, Lihua Qiu, Zhengzi Qian, Bin Meng, Wenchen Gong, Shiyong Zhou, Xianhuo Wang, Huilai Zhang

Published in

Frontiers in immunology. Volume 17. Pages 1790664. Epub Jul 10, 2026.

Abstract

Peripheral T-cell lymphoma (PTCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin lymphoma. Approximately 30% of patients develop relapsed or refractory PTCL (R/R PTCL) due to disease recurrence or failure to achieve complete remission after first-line therapy. Despite therapeutic advances, the molecular and cellular mechanisms underlying treatment resistance in R/R PTCL remain unclear.
Single-cell RNA sequencing and single-cell T-cell receptor sequencing were performed on seven tumor samples from six patients with R/R PTCL. These approaches were used to systematically characterize the transcriptional profiles of malignant T-cell clones and reactive T lymphocytes, define the transcriptomic landscape of R/R PTCL, and identify potential epigenetic biomarkers associated with drug response.
We observed significant upregulation of genes associated with cell proliferation, oncogenic signaling, and immune modulation in R/R PTCL. Within the tumor microenvironment, specific protumorigenic ligand-receptor interactions were identified, including CXCL13-CXCR5, CCL5-CCR5, and CD74-MIF interactions, which may facilitate immune evasion by malignant T cells. Longitudinal analysis of a patient who progressed following dual epigenetic therapy revealed marked downregulation of immune response-related genes, including HLA-DRA/DPA1/DRB5, CD74, C1QC, and LYZ, as well as functional reprogramming of tumor-associated macrophages. Enhanced LGALS9-HAVCR2 and CSF1-CSF1R interactions were also observed following combination treatment with chidamide and azacitidine.
This study delineates the transcriptional heterogeneity of malignant T-cell clones in R/R PTCL and suggests that this heterogeneity may contribute to resistance to epigenetic therapies. These findings provide novel insights into the molecular mechanisms underlying treatment resistance and highlight potential avenues for therapeutic intervention in R/R PTCL.

PMID:
42500655
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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