Immune Cells and Immunotherapy for Cardiac Injury and Repair

Abstract

Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.

Keywords: fibrosis; heart disease; immunology; immunotherapy.

Figure 1.. Immune cell involvement after cardiac injury.

Numerous immune components are involved in the injured myocardium. The main components are represented here. Stressed cells initiate inflammatory secretory programs through the cytosolic DNA sensing cGAS-STING pathway. Dying cells release damage associated patterns (DAMPs) which act as potent signaling molecules. C-reactive protein (CRP), IgM, and other circulating factors permeate the injured heart. Tissue-resident macrophages proliferate and additional CCR2⁺ monocytes are recruited from circulation. Macrophages polarize between M1-like (inflammatory) and M2-like (reparative) phenotypes. Dendritic cells are potent activators of recruited T cells, which are major immune infiltrates. CD8⁺ cytotoxic and several effector T (T_eff) cells signal with M1 macrophages and many other pro-inflammatory pathways. In contrast some T_eff and regulatory T cells (T_reg) infiltrate the heart and stimulate M2-like macrophages, ECM remodeling and overall heart repair. B cells produce many chemokines, cytokines, and autoantibodies. Natural killer (NK) cells are recruited and play a mainly reparative role. Many neutrophils are recruited where they stimulate M1-like macrophages and secrete pro-inflammatory cytokines. Eosinophils also infiltrate the heart and help stimulate tissue recovery. One of the major downstream targets of this inflammatory milieu are cardiac fibroblasts. Tissue-resident fibroblasts proliferate and activate and produce detrimental fibrosis.

Figure 2.. Potential immune-modulating targets to promote cardiac repair.

Many immune modulatory targets exist within the complex signaling network in the injured myocardium. Chimeric antigen receptor (CAR) constructs include antigen recognition domains and intracellular signaling domains, which are engineered into cytotoxic T cells. CAR T cells designed against activated fibroblasts and senescent cells both offer exciting directions to improve cardiac repair in the failing heart. Shifting the balance of macrophage polarization to favor the M2-like, reparative phenotype, may produce beneficial effects. Limiting the cytotoxic CD8⁺ and heart-specific CD4⁺ T cell infiltrate in favor of boosting regulatory (T_reg) cells, beneficial subsets of effector T (T_eff) cells and natural killer (NK) cells have each been shown to benefit cardiac repair. Similarly, shifting the balance to eosinophils over neutrophils may benefit recovery. Disrupting B cell pathways offers potential benefit. Targeted interleukin blockade (IL-1, IL-11, IL-15, TGFβ, etc.) or reparative cytokine (IL-10) administration may limit damage of excessive (or improperly timed) inflammation. Lastly, the development of novel chemical materials and biological interventions (including miRNAs and exosomes) offer exciting targeted immune modulators.