Dendritic cell lysosomes in immune checkpoint inhibitor-associated myocarditis

/ABSTRACT This project has two overarching goals: (1) to investigate the role of dendritic cell (DC) lysosome activity in immune checkpoint inhibitor (ICI)-associated myocarditis, and (2) to serve as a platform for further research and career training of the PI, Dr. Kenji Rowel Lim, to transition to independence. Although tremendously successful, ICIs in cancer therapy induce several immune-related adverse effects. ICI myocarditis is a highly fatal disease of inflammation-induced cardiac injury, with its incidence expected to rise due to improved diagnosis and in- creased ICI use in the clinic. Effective treatments are unavailable and urgently needed. Research has tradition- ally focused on how unrestrained autoreactive T cell activation from loss of immune checkpoint inhibition fuels ICI myocarditis. Preliminary work by the PI suggests that DCs, which take up and present antigens to T cells for activation, are also affected under these conditions, highlighting a previously unexplored layer of complexity in this disease. In particular, the PI found that DC lysosomes had reduced activity in the absence of immune check- point inhibition. Based on these data, it is hypothesized that reduced DC lysosomal activity in ICI myocarditis leads to reduced degradation of internalized antigens, better preserving epitopes, enhancing presentation, and increasing T cell activation. This hypothesis will be tested by characterizing differences in lysosomal activity between wild-type DCs and DCs deficient in the immune checkpoint receptor PD-1 (PD-1 KO), and establishing a connection between PD-1 signaling and lysosomal activity (Aim 1); determining if reducing lysosomal activity in DCs provokes myocarditis in the setting of cardiac injury (Aim 2); and determining if enhancing lysosomal activity in PD-1 KO DCs prevents ICI myocarditis (Aim 3). This project will advance understanding of ICI myo- carditis biology and uncover potential therapies for this disease. The PI has extensive research experience in molecular biology, genetics, and cardiac immunology, from previous Ph.D. training in Canada and postdoctoral training with Drs. Abhinav Diwan and Douglas Mann. The PI seeks to acquire additional training via a mentored approach to complete the proposed work and transition to independence. In their career development plan, the PI aims to: (1) acquire further scientific training in immunology and lysosomal biology to enable the pursuit of innovative cardiac immunology research, (2) acquire training in leadership, mentoring, lab management, and grant writing to become an effective principal investigator, and (3) actively prepare to secure a faculty position at a top-tier research institution. In addition to their primary mentor (Dr. Diwan) and co-mentor (Dr. Mann), the PI will be mentored by a team of leading experts in cardiac immunology (Dr. Sumanth Prabhu, Dr. Pilar Alcaide), and lysosomal biology (Dr. Marco Sardiello), who will also advise on career development. With the exceptionally supportive research environment at Washington University in St. Louis, this training experience will enable the PI’s successful transition to becoming an independent investigator, advancing knowledge on how the immune system shapes the heart, and using this understanding to develop novel, effective therapies for cardiac disease. Project Number: 1K99HL177417-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Kenji Rowel Lim | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $112,822 | Activity Code: K99 | Study Section: NHLBI Mentored Transition to Independence Study Section[MTI (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL17741701A1