HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes

HPV-16 E6 and E7 oncoproteins impair the cell cycle in human uterine cervix carcinoma cells (HUCC) by acting on p53 and retinoblastoma proteins, respe ctively. We recently reported that E7 released into the extracellular compa rtment by HUCC SiHa cells could inhibit immune T-cell response to recall an d alloantigens by a mechanism involving an overproduction of the immunosupp ressive IFN alpha by antigen presenting cells (APCs). In this study, we fou nd that besides E7, E6 protein and the vascular endothelium growth factor ( VEGF) were released into the SiHa cell supernatants, and we further showed that extracellular E7 but not E6 oncoprotein 1) inhibits the immune cell re sponse to recall and alloantigens, and 2) enhances the release of angiogeni c cytokines, including TNF alpha, IL-1 beta and IL-6 by macrophages and/or dendritic cells. VEGF unexpectedly released by cancer cells could also cont ribute to angiogenesis. Thus in HUCC the same E7 oncoprotein which contribu tes to controlling the cancer cell cycle has the means in its extracellular configuration to contribute to microenvironmental immunosuppressive and an giogenic processes. Neutralizing anti-E7 antibodies either passively admini stered of induced by active immunization could represent a new immunotherap eutic endeavour to combat the immunosuppression and/or neoangiogenesis effe cts of extracellular E7 protein. (C) 1999 Editions scientifiques et medical es Elsevier SAS.