Fibrotic Rewiring of CD8+ T Cells by Doxorubicin Drives Pathological Remodeling of Cardiac Extracellular Matrix.

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.