MSTP student Washington University School of Medicine, St. Louis, United States
Disclosure(s):
Steven Yang, BA: No financial relationships to disclose
Introduction/Rationale: Cardiac fibrosis is a major driver of heart-failure progression, yet no approved therapies directly target fibrotic remodeling. Recent work has identified a population of activated, non-myofibroblast cardiac fibroblasts marked by fibroblast activation protein (FAP). These FAP+ fibroblasts arise after injury through inflammatory signaling and contribute to pathological fibrosis.
Methods: We utilized an echo guided model of cardiac ischemia reperfusion injury to investigate the effects of of FAP+ fibroblast depletion. We also evaluated the therapeutic feasibility of FAP-directed bispecific T-cell–engaging antibodies (BiTE® molecules) to eliminate FAP+ fibroblasts and profiled downstream signaling pathways. Finally, we investigated strategies for reducing harmful collateral inflammation from BiTE® molecule treatment while preserving the cardioprotective effects of FAP+ fibroblast depletion.
Results: We demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE® molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced adverse remodeling, and increased scar size. FAP BiTE® molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion.
Conclusion: We reveal that IFNg signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE® molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE® molecules and inform the design of the next generation of therapeutics.
