Fibrotic Rewiring of CD8+ T Cells by Doxorubicin Drives Pathological Remodeling of Cardiac Extracellular Matrix
5 affiliations
- 1Tufts University School of Medicine, Boston, Massachusetts, USA
- 2Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
- 3Department of Cardiology, German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany
- 4Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- 5Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
Abstract
Background: Anthracycline chemotherapy can lead to cardiotoxicity and chronic heart failure, and specific preventative therapies are nonexistent to date. As such, mechanistic investigation is needed to develop cardioprotective strategies. We previously showed that the anthracycline doxorubicin elicits a cardiotropic CD8+ T-cell response that contributes to cardiac fibroblast transformation, fibrosis, and chronic cardiotoxicity. However, the exact molecular mechanisms of T-cell–induced fibrosis, and whether T cells can directly induce cardiac remodeling, remain unknown.
Objectives: We sought to investigate T-cell transcriptomes from anthracycline-treated patients, mice, and cultured T cells to better understand mechanisms by which T cells influence adverse cardiac remodeling upon doxorubicin treatment across species.
Methods: We combined bulk RNA sequencing of human circulating CD8+ T cells from patients before or 3 months after anthracycline treatment with single-cell RNA sequencing of murine doxorubicin- or PBS-treated cardiac CD8+ T cells. Primary murine T cells were treated with doxorubicin in vitro for molecular mechanistic studies, and ex vivo mechanical characterization was performed on cardiac extracellular matrix (ECM).
Results: Anthracycline treatment induces novel profibrotic signature characterized by higher expression of ECM and ECM-crosslinking proteins in human and murine CD8+ T cells, which we term “matrix remodeling T cells” (mxT-cells). Functional mechanical testing of cardiac ECM revealed that mxT-cells stiffen cardiac ECM through T-cell lysyl oxidase (LOX) activity. Mechanistically, doxorubicin activates HIF1α-P53 signaling in mxT-cells, inducing autocrine TGFβ1 that enhances LOX and results in ECM crosslinking and elevated cardiac stiffness.
Conclusions: Our data demonstrate that doxorubicin imprints a novel intrinsic profibrotic function in CD8+ T cells responsible for ECM crosslinking, fibrosis, and cardiac remodeling.
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BibTeX
@article{bayer2026fibrotic,
title = {{Fibrotic Rewiring of CD8+ T Cells by Doxorubicin Drives Pathological Remodeling of Cardiac Extracellular Matrix}},
author = {Abraham L. Bayer and Ramona Emig and Celina Kley and Maria Antonia Zambrano and Zachary L. Robbe and Jose Max Narvaez-Paliza and Sanam Alilou and Sarah Powers and Jenica N. Upshaw and Aarti Asnani and Pilar Alcaide},
journal = {JACC: CardioOncology},
year = {2026},
month = oct,
doi = {10.1016/j.jaccao.2026.09.001},
url = {https://doi.org/10.1016/j.jaccao.2026.09.001},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Fibrotic Rewiring of CD8+ T Cells by Doxorubicin Drives Pathological Remodeling of Cardiac Extracellular Matrix
AU - Abraham L. Bayer
AU - Ramona Emig
AU - Celina Kley
AU - Maria Antonia Zambrano
AU - Zachary L. Robbe
AU - Jose Max Narvaez-Paliza
AU - Sanam Alilou
AU - Sarah Powers
AU - Jenica N. Upshaw
AU - Aarti Asnani
AU - Pilar Alcaide
PY - 2026
DA - 2026/10/01
JO - JACC: CardioOncology
DO - 10.1016/j.jaccao.2026.09.001
UR - https://doi.org/10.1016/j.jaccao.2026.09.001
AB - Background: Anthracycline chemotherapy can lead to cardiotoxicity and chronic heart failure, and specific preventative therapies are nonexistent to date. As such, mechanistic investigation is needed to develop cardioprotective strategies. We previously showed that the anthracycline doxorubicin elicits a cardiotropic CD8+ T-cell response that contributes to cardiac fibroblast transformation, fibrosis, and chronic cardiotoxicity. However, the exact molecular mechanisms of T-cell–induced fibrosis, and whether T cells can directly induce cardiac remodeling, remain unknown. Objectives: We sought to investigate T-cell transcriptomes from anthracycline-treated patients, mice, and cultured T cells to better understand mechanisms by which T cells influence adverse cardiac remodeling upon doxorubicin treatment across species. Methods: We combined bulk RNA sequencing of human circulating CD8+ T cells from patients before or 3 months after anthracycline treatment with single-cell RNA sequencing of murine doxorubicin- or PBS-treated cardiac CD8+ T cells. Primary murine T cells were treated with doxorubicin in vitro for molecular mechanistic studies, and ex vivo mechanical characterization was performed on cardiac extracellular matrix (ECM). Results: Anthracycline treatment induces novel profibrotic signature characterized by higher expression of ECM and ECM-crosslinking proteins in human and murine CD8+ T cells, which we term “matrix remodeling T cells” (mxT-cells). Functional mechanical testing of cardiac ECM revealed that mxT-cells stiffen cardiac ECM through T-cell lysyl oxidase (LOX) activity. Mechanistically, doxorubicin activates HIF1α-P53 signaling in mxT-cells, inducing autocrine TGFβ1 that enhances LOX and results in ECM crosslinking and elevated cardiac stiffness. Conclusions: Our data demonstrate that doxorubicin imprints a novel intrinsic profibrotic function in CD8+ T cells responsible for ECM crosslinking, fibrosis, and cardiac remodeling.
SN - 2666-0873
ER -