Role of reactive oxygen species in immune suppression in cancer (49.12)

Abstract

Abstract The inability of the host immune system to develop and maintain an effective anti-tumor immune response is one of the main mechanisms of tumor progression. Recent findings suggested that hyper-production of reactive oxygen species (ROS) by myeloid cells in cancer may be one of the major factors responsible for T-cell non-responsiveness. However, the mechanism of ROS accumulation as well as their precise role in immune defects in cancer remains unclear. Previous reports have also stated that myeloid-derived suppressive cells (MDSC) contain increased levels of active STAT3 and we set out to address the relationship, if any, between STAT3 and the observed high ROS production. Our data indicate that MDSC isolated from tumor-bearing mice have a significant increase in the expression of two critical components of NADPH oxidase: gp91phox and p47phox than their wild type counterparts. The NADPH oxidase has long been considered a strong source of ROS in myeloid cells and we suggested that STAT3 may be partially responsible for this up-regulation. Our results show that STAT3 does indeed binds to the promoter region of the p47 gene. Furthermore, in vitro inhibition of STAT3 decreased the expression of both gp91phox and p47phox. In addition, the presence of an active NADPH complex was critically important for MDSC-mediated immune suppression. Tumor-bearing mice with defective NADPH oxidase had significantly lower presence of MDSC than their wild-type counterparts. MDSC from gp91phox KO mice had significantly lower suppressive activity against antigen-specific T cells than MDSC isolated from wild-type tumor-bearing mice. Arginase activity and nitric oxide production, factors implicated to mediate MDSC-mediated immune suppression, were also decreased in gp91phox KO mice. These findings may help to clarify the role of ROS in cancer and to develop new effective cancer treatment.