# Low-Intensity Exercise Attenuates Immune Checkpoint Inhibitor-Induced Cardiotoxicity via Regulation of Metabolism and Autophagy

## TL;DR

Low-intensity exercise can protect the heart from damage caused by a cancer treatment called immune checkpoint inhibitors.

## Contribution

This study shows low-intensity exercise protects against immune checkpoint inhibitor-induced heart damage by regulating metabolism and autophagy.

## Key findings

- Mice treated with anti-PD-1 showed heart dysfunction, but those exercising had preserved cardiac function.
- Low-intensity exercise regulated dysfunctional metabolism and autophagy in ICI-treated mice.
- Exercise protected against ICI-induced cardiotoxicity through regulation of protein synthesis and degradation.

## Abstract

Immune checkpoint inhibitors, such as anti-PD-1, are a relatively new and very effective cancer treatment, but in rare cases patients can suffer from cardiac remodeling and damage, leading to reduced cardiac function that is difficult to diagnose and treat. In this study, we found that mice treated with anti-PD-1 immune checkpoint inhibitors developed cardiac remodeling and dysfunction, while mice that performed low-intensity exercise concurrent with anti-PD-1 treatment showed preserved cardiac function and protection against abnormal cellular signaling pathways. These findings suggest that low-intensity exercise may be a safe and feasible adjuvant treatment option to help protect the heart in patients receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) are a new anti-cancer therapy that have improved survival rates in many aggressive cancers. However, while rare, a significant number of patients develop ICI-induced cardiotoxicity. Clinical manifestations are non-specific and underlying cellular mechanisms remain unknown, making diagnosis and treatment of these ICI-induced cardiac side effects difficult. Exercise has shown protective effects against chemotherapy-induced cardiotoxicity but has not been investigated in combination with ICIs. High-intensity exercise has shown greatest cardioprotective effects in preclinical (animal) models, but human cancer patients prefer low-intensity exercise in the clinical setting. Therefore, the purpose of this study was to further identify the cardioprotective effects of low-intensity exercise as a treatment strategy against ICI-induced cardiotoxicity. Methods: Female mice were randomly selected and separated into four groups: sedentary (SED), sedentary ICI-treated (SED + ICI), low-intensity treadmill-exercised (TM), and low-intensity treadmill-exercised ICI-treated mice (TM + ICI). Mice either underwent a 4-week low-intensity treadmill exercise protocol (TM) or remained sedentary (SED). During the 4 weeks, ICI mice received anti-PD-1 treatment (200 μg/mouse) via intraperitoneal injections twice each week. Echocardiography was performed at baseline and sacrifice to determine changes in cardiac structure and function. At sacrifice, cardiac tissue was collected, weighed, and frozen for further biochemical analysis. Underlying metabolic signaling pathways were assessed via Western Blot, and autophagic flux was analyzed via fluorescent microscopy. Results: Echocardiography at sacrifice revealed significantly decreased fractional shortening as a measure of cardiac function (−20%), 1.5-fold dilation of the left ventricle, and thinning of the posterior cardiac wall at systole and diastole in SED + ICI mice compared to SED controls (p < 0.05), indicative of a phenotype of ICI-induced dilated cardiomyopathy. TM + ICI mice did not show a significant difference in these cardiac structural and functional parameters, suggesting cardioprotective effects of low-intensity exercise. In line with these findings, Western Blot and fluorescent microscopy analyses revealed upregulation of autophagic flux (p < 0.05), as well as dysfunctional metabolic pathways (p < 0.05) in ICI-treated mice compared to non-ICI controls. Low-intensity exercise was associated with regulation of dysfunctional metabolism and autophagy in TM + ICI compared to SED + ICI mice. Conclusions: The clinically relevant ICI treatment protocol used in this study led to significant cardiac dysfunction and remodeling, accompanied by underlying dysfunctional metabolism and autophagy. Low-intensity exercise was capable of regulating abnormal protein synthesis and degradation and protecting against ICI-induced cardiotoxicity. This study adds knowledge to the characterization of still unclear clinical manifestations of ICI-induced cardiotoxicity, underlying signaling pathways that could shed light on potential pharmacological treatment targets, as well as the protective effects of low-intensity exercise as a non-pharmacological treatment strategy.