Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines.
Dendritic cell (DC)-based vaccines have exhibited minimal effectiveness in treating established tumors, likely because of factors present in the tumor microenvironment. One such factor is transforming growth factor beta (TGF-beta), a cytokine that is produced by numerous tumor types and has been demonstrated to impair DC functions in vitro. We have evaluated the effect of TGF-beta on the immunostimulatory activities of DCs. We demonstrate that TGF-beta exposure inhibits the ability of DCs to present antigen, stimulate tumor-sensitized T lymphocytes, and migrate to draining lymph nodes. Neutralization of TGF-beta using the TGF-beta-neutralizing monoclonal antibody 2G7 enhanced the ability of DC vaccines to inhibit the growth of established 4T1 murine mammary tumors. Treatment of 4T1 tumors transduced with the antisense TGF-beta transgene (4T1-asT) with the combination of DC and 2G7 monoclonal antibody inhibited tumor growth and resulted in complete regression of tumors in 40% of the mice. These results demonstrate that neutralization of TGF-beta in tumor-bearing mice enhances the efficacy of DC-based vaccines.
Kobie
James J
JJ
Department of Microbiology and Immunology, University of Arizona, Tucson, Arizona 85724, USA.
Wu
Rita S
RS
Kurt
Robert A
RA
Lou
Sunming
S
Adelman
Miranda K
MK
Whitesell
Luke J
LJ
Ramanathapuram
Lalitha V
LV
Arteaga
Carlos L
CL
Akporiaye
Emmanuel T
ET
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016373:DNA, Antisense / Q000235:genetics / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D016373:DNA, Antisense; D016212:Transforming Growth Factor beta