Peptide inhibitors of transforming growth factor-beta enhance the efficacy of antitumor immunotherapy
Llopiz D, Dotor J, Casares N, Bezunartea J, Díaz-Valdés N, Ruiz M, Aranda F, Berraondo P, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P.
Division of Hepatology and Gene Therapy, University of Navarra, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Transforming growth factor-beta (TGF-beta) is a cytokine with potent immunosuppressive effects and is overexpressed in many tumors.
Therefore, development of molecules able to inhibit TGF-beta is of paramount importance to improve the efficacy of antitumor immunotherapy. TGF-beta 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-beta inhibitor peptides.
Simultaneous administration of adjuvants and TGF-beta inhibitor peptides was required for maximal therapeutic efficacy. Although tumor cells produced TGF-beta, it was found that the beneficial effect of peptide administration was mainly due to the inhibition of TGF-beta 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-beta in therapeutic vaccination enhances the efficacy of immunotherapy by increasing antitumor immune responses.
These peptide inhibitors may have important applications for current immunotherapeutic strategies.
CITATION Int J Cancer. 2009 Dec 1;125(11):2614-23