Purpose: Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4⁺ and CD8⁺T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti–TGF-β (1D11) and a peptide vaccine on induction of antitumor immunity, and the mechanisms accounting for synergistic efficacy.

Experimental Design: The effect of combination treatment with a peptide vaccine and anti–TGF-β was examined in a subcutaneous TC1 tumor model, as well as the mechanisms of protection induced by this treatment.

Results: Anti–TGF-β significantly and synergistically improved vaccine efficacy as measured by reduction in primary tumor growth, although anti–TGF-β alone had no impact. The number of tumor antigen–specific CTL with high functional avidity as measured by IFN-γ production and lytic activity was significantly increased in vaccinated mice by TGF-β neutralization. Although TGF-β is known to play a critical role in CD4⁺Foxp3⁺ Treg cells, Treg depletion/suppression by an anti-CD25 monoclonal antibody (PC61) before tumor challenge did not enhance vaccine efficacy, and adding anti–TGF-β did not affect Treg numbers in lymph nodes or tumors or their function. Also, TGF-β neutralization had no effect on interleukin-17–producing T cells, which are induced by TGF-β and interleukin-6. Absence of type II NKT cells, which induce myeloid cells to produce TGF-β, was not sufficient to eliminate all sources of suppressive TGF-β. Finally, the synergistic protection induced by anti–TGF-β vaccine augmentation was mediated by CD8⁺ T cells since anti-CD8 treatment completely abrogated the effect.

Conclusions: These results suggest that TGF-β blockade may be useful for enhancing cancer vaccine efficacy. (Clin Cancer Res 2009;15(21):6560–9)