Unraveling the role of immune cells underlying the cardiotoxic effects of Immune Checkpoint Inhibitor Therapies

Heart failure (HF) is a complex clinical condition that develops when the heart does not pump enough blood to meet the body’s needs. Recently, several studies have shown that chronic release of pro-inflammatory cytokines in the myocardium plays a key role in the maladaptive tissue remodeling and cardiac dysfunction, leading to HF. Patients with chronic HF have elevated levels of circulating pro-inflammatory cytokines which provided evidence of an ongoing inflammatory response in the total absence of infectious agents or autoimmune triggers, also known as sterile inflammation. This process is triggered by a progressive infiltration of immune cells in the heart, but their role is largely uncharacterized. Interestingly, Martini et al. have deeply explored the specific contribution of immune cells in a mouse model of pressure overload-induced HF identifying different subset of cells through a single-cell approach. Among the populations, programmed cell death protein 1 (PD-1) was selectively expressed on cardiac regulatory T cells, whose dysfunction is associated with an induction of immune activation and HF development. Similarly to PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is an evolutionarily conserved cell surface protein molecule that negatively regulates T-cell activation, maintaining peripheral tolerance and preventing autoimmunity. Recently, the development of immune-checkpoint inhibitors (ICIs) targeting CTLA4 or PD-1/PD-L1 molecules has dramatically revolutionized antineoplastic treatments, enabling tumor-reactive T-cells to overcome regulatory mechanisms and mount an effective antitumor response. However, Lars Michel and colleagues showed that abrogation of immune checkpoint signaling follows with severe immune-related adverse events (irAEs), including cardiovascular manifestations. Myocarditis represents the most prevalent ICI-related cardiotoxic effect and, although rare, it is lethal in the 50% of the patients. To better understand the mechanisms behind these cardiotoxic effects, Spencer C. Wei and collaborators generated a robust preclinical mouse model that recapitulates ICI-associated myocarditis syndrome in patients. Experiments carried out in this animal model, characterized by the monoallelic loss of Ctla4 and Pdcd1 knock-out, suggest that those genes functionally interrelate for myocarditis development in a dose-dependent manner. Overall, these findings suggest that sterile inflammation caused by severe infiltration of immune cells plays a central role in the HF progression. This is particularly relevant in the case of the use of ICI therapy targeting PD-1 that leads to a severe disruption of immune cardiac homeostasis, eliciting the development of myocarditis. Owing to the previously generated mouse model, a therapeutic approach that mitigates the lethal course of ICI myocarditis by intervention with CTLA4 agonist abatacept was developed.