The long-term objective of this project is to understand the regulation of FcgammaR-mediated functions such as phagocytosis and ADCC, both important defense mechanisms in cancer. Antibodies form an important link between humoral and cell-mediated immunity. The Fc region of the antigen-complexed antibody serves to activate FcR-bearing effector cells to antigenic challenge. Indeed this basic principle has been elegantly exploited by cancer biologists to develop antibody-mediated therapeutic approaches. In murine models of antibody therapy, it has been clearly demonstrated that anti-tumor antibodies work by recruiting and activating Fc receptor-bearing effector cells, predominantly monocytes/macrophages, leading to the destruction of the tumor cells. Thus, it is critical to understand the molecular details of macrophage FcgammaR expression and function to develop strategies to enhance the efficacy of anti-tumor antibodies. Our work in the last several years has revealed two critical findings, i.e that Fc receptor-mediated macrophage functions are critically regulated by phosphatases through their influence on Akt, and that the expression of the activating and the inhibiting Fc receptors is differentially regulated by mediators present in the surrounding milieu leading to altered functional outcomes. Thus in the current grant proposal we propose the following three specific aims: 1) to examine the unexpected role of Akt on Fcgamma receptor- mediated macrophage activation events leading to phagocytosis and ADCC against antibody-coated tumor cells, 2) to examine the influence of Akt on phagocytosis-associated inflammatory events such as cytokine production and the generation of reactive oxygen species, and 3) to investigate the influnec of TGFbeta and CpG ODN on Fcgamma receptor expression and function. A thorough understanding of monocyte/macrophage Fcgamma receptor expression and function will likely identify better immunotherapeutic strategies to enhance the efficacy of monoclonal antibodies in cancer therapy. Given our interactions with the other Projects and the Cores of this Program Project, we are optimally poised to unravel the molecular details of monocyte/macrophage biology as it pertains to Fc receptor-mediated functional outcomes.
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