Cardiovascular diseases (CVDs) are the number one cause of death globally, responsible for 31% of all human mortalities. This is in part due to lifestyle but also because the human heart is incapable of functional regeneration following injury or onset of disease. In contrast, cardiac regeneration can occur in lower vertebrates and was first identified in zebrafish where surgical resection of the adult heart leads to complete regeneration within 60 days (1). Remarkably, it was later shown that the hearts of neonatal mice could also fully regenerate following the removal of 15% of the left ventricle (2). In both cases, the regenerative response is a result of proliferation of pre-existing cardiomyocytes with complete regression of fibrosis (scarring) (2,3,4).
In a recent paper, Aghajanian et al (5) have taken advantage of the “Immunorevolution” and current breakthroughs in cancer therapy achieved by redirecting cytotoxic T cells to recognize specific antigens on cancer cells using either a modified T cell receptor or a chimeric antigen receptor (CAR) (6). In the current paper, it was hypothesized that engineered T cells could also be used to target cardiac fibroblasts and ultimately eliminate excessive fibrosis in the heart. Proof-of-principle was carried out by the generation of a mouse model in which a xenogeneic marker (ovalbumin peptide, OVA) was expressed on cardiac fibroblasts following cardiac injury induced by fusion of angiotensin II and phenylephrine (AngII/PE). In these mice, significant fibrosis was observed in the myocardium, consistent with previous reports (7). When retrovirus transduced CD8+ T cells expressing a cognate T cell receptor against OVA were administered to the mice, significantly less cardiac fibrosis and cardiac hypertrophy were observed, demonstrating immune-targeting and depletion of activated cardiac fibroblasts is possible. However, since any effective treatment would need to target endogenous proteins specifically expressed on cardiac fibroblasts, gene-expression data from human heart samples was analysed to identify fibroblast-specific genes upregulated in the myocardium of patients with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). To this end, the cell-surface glycoprotein FAP (8) was identified by immunostaining as a target and shown to be specifically upregulated following cardiac injury. Using the above AngII/PE model, retroviral transduced “FAP’’ CAR T cells were administered, and hearts analysed after 4 and 8 weeks. In both cases, there was a clear reduction in fibrosis and a partial rescue of both systolic and diastolic cardiac function in injured mice treated with FAP CAR T cells compared to controls.
In summary, this work reveals a proof-of-concept for the possibility of using engineered T cells to target and treat a disease state other than cancer, namely cardiac fibrosis. While no obvious increases in cytokine levels, myocardial toxicity or inflammatory markers were observed, much work is still necessary before this approach can be translated into humans. Further, while reducing fibrosis in models of myocardial disease has previously been shown to reduce fibrosis and improve function in mice (7,9), we are still left with the problem that the adult human heart cannot regenerate due to a lack of cardiomyocyte proliferation.
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- Poss KD, et al. Heart regeneration in zebrafish. Science. 2002; 298:2188–2190.
- Porrello ER, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011; 331:1078–1080.
- Kikuchi K, et al. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature. 2010; 464:601–605.
- Jopling C, et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010; 464:606–609.
- Aghajanian H, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019; 573: 430–433.
- June, C. H, et al. CAR T cell immunotherapy for human cancer. Science. 2018; 359: 1361–1365.
- Kaur, H., et al. Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. Circulation research. 2016; 118: 1906–1917.
- Scanlan, M. J., et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Clinical Genetic. 2012; 82(4):367-73.
- Kanisicak, O., et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nature Communication. 2016; 7: 12260.