Expression of a soluble TGF-beta receptor by tumor cells enhances dendritic cell/tumor fusion vaccine efficacy.
Dendritic cell (DC)-based antitumor immunotherapy is a promising cancer therapy. We have previously shown that tumor-derived TGF-beta limits the efficacy of the DC/tumor fusion vaccine in mice. In the current study we investigated the effect of neutralizing tumor-derived TGF-beta on the efficacy of the DC/tumor fusion vaccine. An adenovirus encoding human TGF-beta receptor type II fused to the Fc region of human IgM (Adv-TGF-beta-R) or a control adenovirus encoding LacZ (Adv-LacZ) was used to express a soluble form of the neutralizing TGF-beta receptor (TGF-beta-R). Murine breast carcinoma cells, 4T1, but not bone marrow-derived DCs, were successfully transfected with Adv-TGF-beta-R (4T1+Adv-TGF-beta-R) using a multiplicity of infection of 300. Immunization with irradiated 4T1+Adv-TGF-beta-R tumor cells conferred enhanced antitumor immunity compared with immunization with irradiated 4T1+Adv-LacZ tumor cells. The DC/4T1+Adv-TGF-beta-R fusion vaccine offered enhanced protective and therapeutic efficacy compared with the DC/4T1-Adv-LacZ fusion vaccine. Because TGF-beta is known to induce regulatory T cells (Tregs), we further showed that the DC/4T1+Adv-TGF-beta-R fusion vaccine induced fewer CD4(+)CD25(+)Foxp3(+) Tregs than the DC/4T1+Adv-LacZ fusion vaccine in vitro and in vivo. The suppressive role of splenic CD4(+)CD25(+) Tregs isolated from mice immunized with DC/4T1+Adv-LacZ was demonstrated using a CTL killing assay. Similar enhanced therapeutic efficacy was observed in murine renal cell carcinoma, RenCa, which expresses a high level of TGF-beta. We conclude that the blockade of tumor-derived TGF-beta reduces Treg induction by the DC/tumor fusion vaccine and enhances antitumor immunity. This may be an effective strategy to enhance human DC-based antitumor vaccines.
Zhang
Min
M
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
Berndt
Bradford E
BE
Chen
Jian-Jun
JJ
Kao
John Y
JY
D000818:Animals; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000737:chemistry / Q000473:pathology / Q000628:therapy*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory; D014162:Transfection
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018125:Receptors, Transforming Growth Factor beta