Margin-enriched CD4⁺ central-memory T cells affect macrophages via ANXA1-FPR1 signaling axis to promote tumor progression in intrahepatic cholangiocarcinoma.

Authors

Zhifeng Jiang, Ao Huang, Runze Miao, Shiyu Zhang, Feiyu Chen, Yang Xu, Jiayan Yan, Lixing Li, Senquan Zhang, Rongkui Luo, Wen Huang, Haixiang Sun, Xinrong Yang, Jian Zhou

Published in

International journal of biological sciences. Volume 22. Issue 13. Pages 7225-7239. Epub Aug 11, 2026.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent liver cancer with a high mortality and recurrence rate, and remains a poorly understood disease. The tumor margin, as the transition zone between normal tissue and tumor, was not appreciated before. We performed mass cytometry (cytometry by time of flight, CyTOF) on 30 samples from iCCA tumor, paratumor and margin tissue. We found that the number of CD4⁺ central memory T cells (CD4⁺ T_cm) increased in the margin zone. Single cell RNA-seq (scRNA-seq) further discovered that CD4⁺ T_cm cells enriched in the margin zone of iCCA exhibited upregulated Annexin A1 (ANXA1) expression. Fibroblasts recruited CD4⁺ ANXA1⁺ T_cm cells via Chemokine (C-C motif) ligand 19 (CCL19)-Chemokine (C-C motif) receptor 7 (CCR7) signaling pathway. The molecular characteristics of CD4⁺ ANXA1⁺ T_cm in iCCA were characterized, and the interactions between these T cells and other cells were determined. Patients with enriched CD4⁺ ANXA1⁺ T_cm cells in the tumor margin exhibited a worse prognosis. Specifically, CD4⁺ ANXA1⁺ T_cm cells could recruit macrophages to the tumor margin and regulate the macrophage polarization via the ANXA1-Formyl Peptide Receptor 1 (FPR1) signaling axis. CD4⁺ ANXA1⁺ T_cm cell-activated macrophages could enhance the invasion and proliferation of tumor cells by exerting different cytokines. In conclusion, our study systematically characterized the features and distribution of CD4⁺ ANXA1⁺ T_cm cells in the margin zone of iCCA. We investigated the potential mechanisms by which CD4⁺ ANXA1⁺ T_cm cells affected tumor progression, and provided novel understanding of the function of these CD4⁺ T_cm cells in iCCA.

PMID:
42695008
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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