Identification of functional murine mitochondrial formyl peptides and their effects on myeloid-derived suppressor...

N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, which effects on neutrophil activation have been extensively studied. Mitochondrial formyl peptides are also known to play a role in tumor immunity, but the molecular mechanism underlying this role remains largely unexplored. Our previous work suggested that tumor-derived mitochondrial formyl peptides promote tumor growth by enhancing myeloid-derived suppressor cell (MDSC)-mediated cytotoxic T-lymphocyte suppression. Therefore, we hypothesized that tumor-derived mitochondrial formyl peptides act directly on bone marrow cells to promote MDSC generation. In this study, we tested this hypothesis by first identifying five functional murine mitochondrial formyl peptides that induced intracellular Ca²⁺ flux and chemotaxis, and then assessing their effects on the in vitro generation of MDSCs from murine bone marrow cells cultured with GM-CSF and IL-6. Addition of mitochondrial formyl peptides resulted in a 5-10% increase in polymorphonuclear-MDSCs along with a corresponding decrease in monocyte-MDSCs. These results indicate that tumor-derived mitochondrial formyl peptides directly influence MDSC generation and corroborate findings from prior in vivo tumor transplantation models.