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Войти в исследования JACC. CardioOncology · 2026
Fibrotic Rewiring of CD8+ T Cells by Doxorubicin Drives Pathological Remodeling of Cardiac Extracellular Matrix.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Bayer Abraham L, Emig Ramona, Kley Celina, Zambrano Maria Antonia, Robbe Zachary L, Narvaez-Paliza Jose Max, Alilou Sanam, Powers Sarah, Upshaw Jenica N, Asnani Aarti, Alcaide Pilar
Аннотация
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.
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.