We hope to understand some of the mechanisms tumors use to affect differentiation of antigen presenting cells from myeloid precursors and inhibit immune system responses. The inability of the host immune system to develop and maintain an antitumor immune response is one of the mechanisms of tumor progression. Dr. Gabrilovich's laboratory has previously described a new mechanism of immune deficiency in cancer associated with defective differentiation of dendritic cells (DC). These findings have been confirmed in many laboratories. Defective DC differentiation is mediated by tumor-derived factors and manifests in decreased production of the mature DCs and accumulation of myeloid-derived suppressive cells (MDSC) able to suppress antigen-specific immune responses. MDSC encounter and present tumor antigens to T cells but, instead of inducing activation and rejection of the tumor, MDSC induce T-cell tolerance and allow tumor growth. MDSC-mediated T-cell suppression has been linked with increased production of reactive oxygen species (ROS) by MDSC. In this proposal, we intend to clarify the mechanisms leading to production of ROS and accumulation of MDSC, and also to confirm that these findings take place in cancer patients as well. Relevance: This study could in time help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies.
| Corzo, Cesar A; Cotter, Matthew J; Cheng, Pingyan et al. (2009) Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182:5693-701 |
