Erythropoietin increases macrophage-mediated suppression in a model of the tumor microenvironment (100.1)

Abstract Erythropoietin (EPO), a glycoprotein that increases RBC production, is used to reverse chemotherapy-induced anemia in cancer patients. Unfortunately some patients have experienced accelerated tumor growth and decreased survival rates. We have been modeling the in vivo tumor microenvironment by culturing murine peritoneal cavity (PerC) cells in vitro. Many tumors have significant leucocyte composition including increased representation of myeloid suppressor cells. When PerC T cells are activated in a macrophage-rich environment such as this their proliferation is suppressed. Interferon-gamma (IFN-g)-triggered inducible nitric oxide synthase (iNOS) expression by macrophages drives T cell suppression via arginine catabolism. Addition of 1-methyl arginine (1-MA), a competitive inhibitor of iNOS, recovers the T cell response. We have studied EPO’s impact upon T cell activation in the PerC macrophage model. Exogenous EPO increased T cell suppression by C57BL/6J (wildtype) macrophages and this effect could be blocked by the addition of 1-MA. EPO’s enhanced suppressive effect was not evident with macrophages from iNOS or IFN-g receptor knockout mice. Studies of BALB/c PerC T cells, which were less susceptible to iNOS-mediated suppression, revealed that EPO had no effect upon T cell activation. These results suggest that exogenous EPO can increase T cell suppression and does so by acting through an IFN-g/iNOS-triggered myeloid cell pathway. Supported by NIH AREA R15-CA136901-01.