Immunomodulatory Therapy for Ischemic Heart Disease

Abstract

Ischemic heart disease is a leading cause of death worldwide, manifested clinically as myocardial infarction (and ischemic cardiomyopathy. Presently, there exists a notable scarcity of efficient interventions to restore cardiac function after myocardial infarction. Cumulative evidence suggests that impaired tissue immunity within the ischemic microenvironment aggravates cardiac dysfunction, contributing to progressive heart failure. Recent research breakthroughs propose immunotherapy as a potential approach by leveraging immune and stroma cells to recalibrate the immune microenvironment, holding significant promise for the treatment of ischemic heart disease. In this Primer, we highlight three emerging strategies for immunomodulatory therapy in managing ischemic cardiomyopathy: targeting vascular endothelial cells to rewire tissue immunity, reprogramming myeloid cells to bolster their reparative function, and utilizing adoptive T cell therapy to ameliorate fibrosis. We anticipate that immunomodulatory therapy will offer exciting opportunities for ischemic heart disease treatment.

Keywords: chimeric antigen receptor; endothelial cells; fibroblasts; fibrosis; immunotherapy; ischemic heart disease; macrophages; myeloid cells; myocardial infarction.

Figure. 1.. Endothelial cell-targeting immunomodulatory therapy.

Neovascularization proceeds by endothelial cell (EC) sprouting and overgrowth, contributing to cardiac repair. Aberrant vascularization compromises blood perfusion and impedes infiltration and activation of reparative immunocytes: EC adhesion is disrupted, inducing dysfunctional interaction between ECs and immunocytes, and dysfunctional EC-derived cytokine and metabolites form an immune-hostile milieu that inhibits repair-favorable immunity. Immunomodulatory therapy by genetic and metabolic approaches to target ECs may promote vessel functions and rewire the tissue microenvironment to foster reparative immunity, facilitating cardiac repair after MI. tLNP, targeted lipid nanoparticles; 2-HG, 2-hydroxyglutarate.

Figure 2.. Immunomodulatory therapy by targeting macrophages.

Pro-inflammatory and pro-resolving macrophages have different roles for cardiac repair after MI, inducing prolong inflammation and inflammation resolution, respectively. Immunomodulatory therapy by genetic or epigenetic reprogramming, metabolic rewiring, or gene editing to modulate polarization and using regenerative myeloid progenitor cells may promote macrophage-mediated cardiac repair after MI. OXPHOS, oxidative phosphorylation; FA, fatty acid.

Figure 3.. Immunomodulatory approaches to target activated fibroblasts.

Activated fibroblasts, i.e., myofibroblasts, exacerbate post-MI cardiac fibrosis through pro-inflammatory response. Immunomodulatory therapy using bi-specific antibodies, CAR-T cells, or tLNP to eliminate FAP⁺ fibroblasts or modulating their cytokine expression profile may recondition the immune microenvironment to improve cardiac repair after MI.

Figure 4.. Immunomodulatory therapy by targeting endothelial cells, macrophages, and fibroblasts for ischemic heart disease.

Tissue immunity is fundamental for cardiac repair in ischemic heart disease, which is subjected to spatiotemporal regulation by ECs, macrophages, and fibroblasts in the injured heart. These cells have spatiotemporal roles for tissue injury and repair after MI. Immunomodulatory therapy by genetic, epigenetic, or metabolic approaches to target these cells may offer exciting opportunities to rewire the tissue microenvironment and foster reparative immunity, facilitating cardiac repair after MI.