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, respectively. We recently reported that E7 related into the extracellular compartment by HUCC SiHa cells could inhibit immune T-cell response to recall and alloantigens by a mechanism involving an overproduction of the immunosuppressive IFN alpha by antigen presenting cells (APCs). In this study, we found 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 response to recall and alloantigens, and 2) enhances the release of angiogenic cytokines, including TNF alpha, IL-1 beta and IL-6 by macrophages and/or dendritic cells. VEGF unexpectedly released by cancer cells could also contribute to angiogenesis. Thus in HUCC the same E7 oncoprotein which contributes to controlling the cancer cell cycle has the means in its extracellular configuration to contribute to microenvironmental immunosuppressive and angiogenic processes. Neutralizing anti-E7 antibodies either passively administered or induced by active immunization could represent a new immunotherapeutic endeavour to combat the immunosuppression and/or neoangiogenesis effects of extracellular E7 protein.
Le Buanec
H
H
Laboratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, Paris, France.
D'Anna
R
R
Lachgar
A
A
Zagury
J F
JF
Bernard
J
J
Ittelé
D
D
d'Alessio
P
P
Hallez
S
S
Giannouli
C
C
Burny
A
A
Bizzini
B
B
Gallo
R C
RC
Zagury
D
D
D016207:Cytokines / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008222:Lymphokines / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009856:Oncogene Proteins, Viral / Q000633:toxicity*; D027383:Papillomaviridae / Q000472:pathogenicity*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000821:virology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016207:Cytokines; C068651:E6 protein, Human papillomavirus type 16; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059731:oncogene protein E7, Human papillomavirus type 16