Peptide inhibitors of transforming growth factor-β enhance the efficacy of antitumor immunotherapy

Abstract

Transforming growth factor-β (TGF-β) is a cytokine with potent immunosuppressive effects and is overexpressed in many tumors. Therefore, development of molecules able to inhibit TGF-β is of paramount importance to improve the efficacy of antitumor immunotherapy. TGF-β inhibitor peptides P144 and P17 were combined with the administration of adjuvant molecules poly(I:C) and agonistic anti-CD40 antibodies, and their effect on the growth of E.G7-OVA established tumors and on antitumor immune response was evaluated. Tumor rejection efficacy of a single administration of adjuvants was enhanced from 15 to 70 % when combined with repeated injections of TGF-β inhibitor peptides. Simultaneous administration of adjuvants and TGF-β inhibitor peptides was required for maximal therapeutic efficacy. Although tumor cells produced TGF-β, it was found that the beneficial effect of peptide administration was mainly due to the inhibition of TGF-β produced by regulatory CD4+CD25+ T cells rather than by tumor cells. The enhanced antitumor effect was accompanied by a higher activity of dendritic cells, natural killer cells and tumor antigen-specific T cells, as well as by a decrease in the number of myeloid-derived suppressor cells. In conclusion, administration of peptide inhibitors of TGF-β in therapeutic vaccination enhances the efficacy of immunotherapy by increasing antitumor immune responses. These peptide inhibitors may have important applications for current immunotherapeutic strategies. © 2009 UICC.