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Though TGF-β inhibition enhances antitumor immunity mediated by CD8+ T cells in several tumor models, it is not always sufficient for rejection of tumors. In this study, to maximize the antitumor effect of TGF-β blockade, we tested the effect of anti-TGF-β combined with an irradiated tumor vaccine in a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine alone in prophylactic setting significantly delayed tumor growth, whereas anti-TGF-β antibodies alone did not show any antitumor effect. However, tumor growth was inhibited significantly more in vaccinated mice treated with anti-TGF-β antibodies compared to vaccinated mice without anti-TGF-β, suggesting that anti-TGF-β synergistically enhanced irradiated tumor vaccine efficacy. CD8+ T-cell depletion completely abrogated the vaccine efficacy, and so protection required CD8+ T cells. Depletion of CD25+ T regulatory cells led to the almost complete rejection of tumors without the vaccine, whereas anti-TGF-β did not change the number of CD25+ T regulatory cells in unvaccinated and vaccinated mice. Though the abrogation of CD1d-restricted NKT cells, which have been reported to induce TGF-β production by MDSC through an IL-13-IL-4R-STAT6 pathway, partially enhanced antitumor immunity regardless of vaccination, abrogation of the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway did not enhance vaccine efficacy. Taken together, these data indicated that anti-TGF-β enhances efficacy of a prophylactic vaccine in normal individuals despite their not having the elevated TGF-β levels found in patients with cancer and that the effect is not dependent on TGF-β solely from CD4+CD25+ T regulatory cells or the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway.