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

• Published in: International journal of cancer 2009-12, Vol.125 (11), p.2614-2623
• Main Authors: Llopiz, Diana, Dotor, Javier, Casares, Noelia, Bezunartea, Jaione, Diaz-Valdes, Nancy, Ruiz, Marta, Aranda, Fernando, Berraondo, Pedro, Prieto, Jesus, Lasarte, Juan Jose, Borras-Cuesta, Francisco, Sarobe, Pablo
• Format: Article
• Language: English
• ISSN: 0020-7136
• DOI: 10.1002/ijc.24656

Transforming growth factor- (TGF-) is a cytokine with potent immunosuppressive effects and is overexpressed in many tumors. Therefore, development of molecules able to inhibit TGF- is of paramount importance to improve the efficacy of antitumor immunotherapy. TGF- 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- inhibitor peptides. Simultaneous administration of adjuvants and TGF- inhibitor peptides was required for maximal therapeutic efficacy. Although tumor cells produced TGF-, it was found that the beneficial effect of peptide administration was mainly due to the inhibition of TGF- 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- in therapeutic vaccination enhances the efficacy of immunotherapy by increasing antitumor immune responses. These peptide inhibitors may have important applications for current immunotherapeutic strategies.