Abstract 365: Ponatinib Triggers Cardiac Inflammation by STAT-3 Dependent Immune Checkpoint Blockade

Abstract

Background: Ponatinib is a potent anticancer tyrosine kinase inhibitor (TKI) with considerable cardiotoxicity. The manifestation of cardiovascular adverse events, including fatal myocardial infarction and congestive heart failure, has hampered its clinical use. Therefore, a better understanding of the mechanism by which ponatinib exerts cardiotoxicity is urgently warranted to efficiently counteract treatment-related adversities. Methods: Wild type C57BL/6, comorbidity mouse model ApoE -/- , and pressure overload (PO) mouse model were used to investigate the cardiotoxic mechanism of ponatinib. Echocardiography was performed to assess cardiac function. Flow cytometry analysis was performed to assess the dynamics of inflammation. Results: We observed that high-fat diet (HFD) fed ApoE -/- mice develop cardiac dysfunction within 2 weeks of ponatinib treatment. An unbiased RNA-Seq analysis revealed significant upregulation of inflammatory genes (CCR1, CCR5, CCL6, CCL8, CCL9, CXCL4) in ponatinib treated hearts. Since ApoE -/- background, and HFD are known confounder of inflammation signal, we validated this observation in naïve C57BL/6 mice. Despite the lack of cardiac dysfunction in ponatinib treated naïve C57BL/6 mice, comprehensive immune profiling depicted upregulation of myocardial inflammation as evident by infiltrated immune cells (CD45 + TNFα + , CD45 + CD11b + F4/80 + Ly6C + CCR2 + , CD45 + Gal1 + ). Interestingly, we also demonstrated the downregulation of immune checkpoints over T cells (TCRαβ + CTLA4 + , TCRαβ + PD1 + ) in ponatinib treated hearts. Next, in the PO mouse model, ponatinib treated mice showed significant cardiac dysfunction with myocardial inflammation as reflected by increased frequencies of inflammatory parameters (TNFα + , IL1β + , IL6 + , MCP1 + , CXCL9 + ). Mechanistically, we demonstrated that ponatinib potentially suppresses PD-L1 expression over cardiomyocytes via inhibition of STAT3, subsequently leading to immune cells mediated myocardial inflammation. Conclusions: These findings uncover a novel mechanism of ponatinib induced cardiac inflammation leading to adverse cardiac function. It also suggests that strategies to attenuate inflammation may be an effective therapy to prevent ponatinib induced cardiac adverse events.