Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species

It is well established that tumor growth is associated with accumulation of immature myeloid cells (ImC). They play an important role in tumor-associated immune suppression. ImC accumulate not only in tumor-hearing hosts but also in immunized, tumor-free hosts or hosts infected with bacterial pathogens. The kinetics of ImC in these mice is different. If in tumor-hearing mice, the number of ImC continues to increase with tumor progression in tumor-free mice after an initial spike, it decreases to the control level. Here, we have investigated the mechanisms of ImC accumulation in tumor-bearing hosts by comparing differentiation of ImC obtained from tumor-free and tumor-bearing mice. In the presence of appropriate growth factors, ImC isolated from tumor-free mice quickly differentiated in vitro into mature dendritic cells (DC), macrophages, and granulocytes. In contrast, differentiation of ImC from tumor-bearing mice was significantly delayed. Similar results were obtained in vivo after adoptive transfer of ImC into naive, congeneic mice. ImC transferred into tumor-bearing recipients failed to differentiate into DC or macrophages. ImC from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC obtained from tumor-free mice. Hydrogen peroxide (11202) but not superoxide radical anions was found to be the major part of this increased ROS production. In vitro experiments demonstrated that scavenging of H2O2 with catalase induced differentiation of ImC from tumor-bearing mice into macrophages. Thus, this is a first demonstration that tumors may prevent differentiation of antigen-presenting cells by increasing the level of endogenous H2O2 in immature myeloid cells.