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.
Immune checkpoint inhibitor (ICI)–associated myocarditis remains one of the most serious immune-related adverse events and can present major challenges after hospital discharge. Although guidelines and expert consensus statements have addressed diagnostic and management strategies in the acute phase, there is a paucity of evidence for post-discharge management and how to address recrudescence of symptoms and/or biomarkers suggesting rebound myocarditis. This review synthesizes evidence on the pathophysiology of ICI myocarditis, including the T cell–macrophage inflammatory loop that sustains smoldering disease, and provides a framework for outpatient management. We address steroid tapering strategies, the taper-flare phenomenon, and evidence for second-line agents and emerging therapies. Practical guidance is provided for biomarker surveillance, cardiac imaging protocols, antimicrobial prophylaxis, and the balance between immunosuppression and infection risk. This review aims to highlight and address significant gaps in cardio-oncology practice by offering clinicians an evidence-informed roadmap for managing this complex patient population.
