Emerging Immune Checkpoint Therapies Reshape the Cardiac Immune Landscape and Promote Myocardial Vulnerability

Project Abstract Immune checkpoint therapies have shown remarkable efficacy across multiple tumor types by amplifying cancer- immunity and boosting T-cell immune response against tumors. As an increasing number of immune checkpoint molecules have been identified, numerous combination therapeutic strategies are under clinical investigation. For instance, the combination of an OX40 agonist and PD-1 inhibitor has been shown to have promising anti- tumor effects in pre-clinical studies and early clinical trials. Despite remarkable therapeutic benefit, it has become evident with increasing clinical usage that these agents elevate the risk of immune-related adverse events (irAEs), especially cardiovascular sequelae. Mitigating irAEs is critical for the establishment of efficacious and safe interventions. Currently, little is understood regarding the cardiac effects of combined OX40 activation and PD- 1 inhibition. In this proposal, the PI aims to investigate 1) how cardiac T-cells respond to combined PD-1 inhibition and OX40 activation and sequentially reshape the cardiac immune landscape; 2) the mechanism by which the reshaped T-cell landscape modulates monocytes recruitment, differentiation and immune cell crosstalk; and 3) investigate mechanisms by which combined OX40 activation and PD-1 inhibition leads to myocardial vulnerability. At the end of this award period, the PI will have generated a deep understanding of how a new combination immunotherapy (OX40 activation and PD-1 inhibition) reshapes the cardiac immune landscape and sensitizes the heart to future injury. The PI will leverage new technologies including spectral flow cytometry, single-cell CITE-seq, TCR-seq and advanced computational biology techniques. The PI will also uncover mechanism-based therapeutic targets to prevent or treat cardiac adverse events elicited by combined OX40 activation and PD-1 inhibition. The career development goal of this proposal is to aid in the PI’s success in becoming an independent investigator. The PI has previously obtained a PhD in tumor immunology and completed 4 years of postdoctoral training in cardiac immunology. The proposed 2-year mentored research time under this award will provide the PI with formal training in cardiac T-cell immunology and cardio-oncology, computational biology, and grant- writing. Additionally, the mentorship team and advisory committee will provide training and advice on management skills, technical skills, and making early career decisions. By completing this award period, the PI will have acquired the skills necessary to become a successful independent researcher.