Abstract 806: PD-1 in Cardiac Immune Responses After Ischemic Injury or Transverse Aortic Constriction

Abstract

Background: Heart failure is associated with inflammation, but the precise immune mechanisms that contribute to cardiomyopathy remain elusive. Myocarditis is a rare toxicity of checkpoint inhibitors, which are oncologic therapies that block signaling through the immunoinhibitory molecule PD-1. We investigated whether PD-1 attenuates cardiac immune responses. Methods: Expression of PD-1 and its ligand PD-L1 on cardiac cell populations were assessed by flow cytometry. The functional implications of PD-1 signaling were determined using PD-1 blocking antibodies (Abs) in two surgical models of cardiac injury: ischemia/reperfusion and transverse aortic constriction (TAC). Ischemic injury was measured by troponin release and histology. Systolic function was assayed by echocardiography, diastolic function by invasive pressure-volume loops, and fibrosis by histology. Results: PD-L1 is expressed on most cardiac endothelial cells and a small fraction of cardiomyocytes. While intracardiac T cells do not express PD-1 under baseline conditions, 15% of both CD4 and CD8 T cells express PD-1 after TAC. Blocking PD-1 signaling after ischemic injury did not affect troponin levels (5.8 ng/ml in mice receiving isotype control (IC) Ab vs 7.8 ng/ml in mice receiving anti-PD-1 Ab, p=0.26), size of infarct (1.6% of ventricular cross-sectional area for IC Ab vs 2.0% for anti-PD-1 Ab, p=0.27), or systolic function (fractional shortening 52.6% for IC Ab vs 53.2% for anti-PD-1 Ab, p=0.92). Similarly, abrogation of PD-1 signaling after TAC did not worsen systolic dysfunction (fractional shortening 36.8% for IC Ab vs 32.4% for anti-PD-1 Ab, p=0.38), diastolic function (dP/dT minimum -9445 mmHg/s vs -10950 mmHg/s, p=0.44; Tau 6.8 ms for IC Ab vs 6.0 ms for anti-PD-1 Ab, p=0.45), or the extent of cardiac fibrosis (1.4% of ventricular cross-sectional area for IC vs 1.7% for anti-PD-1 Ab, p=0.41). Conclusion: Collectively, these data do not implicate PD-1 as an important regulator of intracardiac immune responses in the injury models tested. This suggests that additional pathways may contribute to myocarditis occurring in cancer patients treated with anti-PD-1 Ab, the identification of which could provide insight into immune mechanisms active in heart failure.