The ASPIRE Path in Molecular Medicine

Immune checkpoint inhibitors (ICIs) block immunoregulatory receptor-ligand interactions; one such pair, programmed cell death 1 (PD-1) receptor and its ligand (PD-L1), stunt T-cell mediated immune responses. Blockade of this interaction by ICI therapy enables antitumor immunity and the potential for durable clinical responses; however, rheumatologic toxicities are widely reported in patients receiving ICIs, suggesting PD-1 blockade negatively impacts bone. My project aims to discover the underlying mechanism of bone loss in both tumor naïve and tumor-bearing mice. I will investigate the immune phenotype in overt bone metastases by inoculating E0771 cells into wildtype and PD-1-/- mice and assessing bone marrow immune infiltration, tumor progression, and skeletal microarchitecture in this bone colonization model. I also will investigate whether CD8+ T cells are required for bone loss observed when PD-1 is inhibited. I will deplete CD8+ T cells in PD-1-/- mice, adoptively transfer specific T cell populations back in, and assess the bone phenotype. Lastly, I will determine if PD-1 in osteoclasts regulates bone metabolism by assessing the bone phenotype in a myeloid specific LysMCre PD-1 floxed mouse model. These studies have the potential to transform clinical care and outcomes for patients receiving ICIs, thereby making my research well-suited for APMM.