Emerging Immune Checkpoint Therapies Reshape The Cardiac Immune Landscape And Promote Myocardial Vulnerability

Immune checkpoint therapies have shown remarkable efficacy across multiple tumor types by amplifying cancer-immunity and boosting T-cell immune response against tumors. As an increasing number of immune checkpoint molecules have been identified, numerous combination therapeutic strategies are under clinical investigation. For instance, the combination of an OX40 (TNFRSF4) agonist and PD-1 (Programmed cell death protein 1) inhibitor has been shown to have promising anti-tumor effects in pre-clinical studies and early clinical trials. Despite remarkable therapeutic benefit, it has become evident with increasing clinical usage that these agents elevate the risk of immune-related adverse events (irAEs), especially cardiovascular sequelae. Mitigating irAEs is critical for the establishment of efficacious and safe interventions. Currently, little is understood regarding the cardiac effects of combined OX40 activation and PD-1 inhibition. In this study, we observed that PD-1 deletion upregulated OX40 expression on cardiac T-cells. Combined PD1 inhibition (Pdcd1 -/- or PD-1 blocking antibody) and OX40 activation (OX40 agonistic antibody) increased the frequency of splenic and cardiac effector memory CD4 + and CD8 + T-cells, inflammatory monocyte and macrophage infiltration into the heart, and enhanced myocardial expression of numerous chemokines and cytokines in both naïve and tumor bearing mice. Intriguingly, persistent increases in cardiac effector memory CD4 + and CD8 + T-cells and inflammatory macrophages was observed at chronic time points suggesting long term effects on the cardiac immune landscape. Furthermore, OX40 activation aggravates angiotensin II and phenylephrine (AngII/PE) infusion induced cardiac hypertrophy, fibrosis and inflammation in Pdcd1 -/- mice suggesting that the reshaped T-cell and macrophage landscape imparts myocardial vulnerability. This study will also uncover mechanism-based therapeutic targets to prevent or treat cardiac adverse events elicited by combined OX40 activation and PD-1 inhibition.