Cancer-associated immunodeficiency and dendritic cell dysfunction: 1. Mediated by the prostaglandin receptor EP2. 2. Myeloid immune suppressor cells in tumor-host interaction

This dissertation research focuses on the effect of PGE2 on dendritic cell differentiation, function and migration in the tumor-bearing host as well as the contribution of myeloid immune suppressor Gr+CD11b+ cells to tumor growth.; Significant data demonstrate the over production of COX-2 and its major metabolite PGE2 in tumor malignancy, as well as the effect of PGE 2 and the EP2 receptor in specific immune populations. We observe an attenuated tumor growth and prolonged survival in EP2-/- mice. We further demonstrate this decreased tumor growth is due to improved DC function and migration in tumor-bearing EP2 -/- animals, compared with that of wt controls. Our studies suggest that PGE2 affects DC differentiation, function and migration through the EP2 receptor. These data suggest that an antagonist of the EP2 receptor may provide a therapeutic approach to improve host anti-tumor immunity, and should be more specific than COX-2 inhibitors.; Myeloid immune suppressor Gr+CD11b+ cells are significantly over produced in tumor-bearing hosts, this is one mechanism of tumor escape from immune system control and compromised efficacy of cancer immunotherapy. In this line of research, we investigated the roles of Gr+CD11b+ cells in tumor growth. We find that Gr+CD11b+ cells directly contribute to tumor growth through the mechanisms of tumor angiogenesis (producing MMP9) and vasculogenesis (differentiating into ECs). Our data show that tumors co-injected with Gr+CD11b+ cells exhibit increased blood vessel density and decreased necrosis. Gr+CD11b+ cells produce very high level of MMP9. Deletion of MMP9 in Gr+CD11b+ cells completely abolishes their tumor-promoting ability. Gr+CD11b+ cells are also found to incorporate directly into tumor vascular endothelium. Consistent with this observation, Gr+CD11b+ cells obtain EC properties in the tumor microenvironment and proangiogenic culture conditions. Our data provide new evidence of the systemic impact of cancers on the host. Therapeutic approaches directed at this aspect of the host-tumor interface may have synergistic immune and antiangiogenic effectiveness.