Exercise Protects Against Anti-PD-1 Immune Checkpoint Inhibitor (ICI) Induced Cardiotoxicity In Female Mice

PURPOSE: ICIs, a new anti-cancer therapy, have improved survival rates in many cancers. However, an increasing number of patients develop ICI-induced cardiotoxicity. Clinical manifestations are nonspecific and underlying cellular mechanisms remain unknown. Exercise has shown protective effects against chemotherapy-induced cardiotoxicity but has not been investigated in combination with ICIs. The purpose of this study was to investigate ICI-induced cardiotoxicity and determine protective effects of low-intensity exercise. METHODS: Mice were separated into 4 groups: sedentary (SED), sedentary ICI (SED + ICI), low-intensity exercised (TM), and low-intensity exercised ICI (TM + ICI). Mice either underwent a 4-week low-intensity exercise protocol (TM) or remained sedentary (SED). During the 4 weeks, ICI mice received ICI treatment (200ug/mouse) via i.p. injections twice/week. Echocardiography was performed at baseline and sacrifice. At sacrifice, cardiac tissue was collected and underlying signaling pathways were assessed via Western Blot. RESULTS: Echocardiography at sacrifice revealed significantly decreased fractional shortening (-20%), 1.5-fold dilation of the left ventricle and thinning of posterior walls at systole and diastole in SED + ICI mice compared to SED controls (P < 0.05), indicative of ICI-induced dilated cardiomyopathy. TM + ICI mice did not show significant declines, suggesting that low-intensity exercise preserved cardiac structure and function. In line with these findings, Western Blot analysis revealed dysfunctional metabolic pathways (P < 0.05) in ICI treated mice. CONCLUSIONS: These data shed light on the previously unrecognized notion that ICI treatment can induce cardiotoxic adverse events. Clinically relevant ICI treatment led to significant cardiac structural and functional changes, accompanied by underlying dysfunctional metabolism. Low-intensity exercise seemed to protect against ICI-induced cardiotoxicity. This study adds knowledge to the characterization of still unclear clinical manifestations of ICI-induced cardiotoxicity and clinically relevant, cardioprotective interventions to protect against ICI-cardiotoxicity.