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

• Published in: International journal of cancer Vol. 125; no. 11; pp. 2614 - 2623
• Main Authors: Llopiz, Diana, Dotor, Javier, Casares, Noelia, Bezunartea, Jaione, Díaz‐Valdés, Nancy, Ruiz, Marta, Aranda, Fernando, Berraondo, Pedro, Prieto, Jesús, Lasarte, Juan José, Borrás‐Cuesta, Francisco, Sarobe, Pablo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2009; Wiley-Blackwell
• Subjects: Adjuvants, Immunologic - therapeutic use; Animals; Biological and medical sciences; CD40 Antigens - immunology; Dendritic Cells - immunology; Female; Flow Cytometry; Homeodomain Proteins - physiology; Humans; Immunotherapy; inhibitor peptides; Killer Cells, Natural - immunology; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin - immunology; Peptide Fragments - pharmacology; Poly I-C - immunology; Poly I-C - therapeutic use; Receptors, Transforming Growth Factor beta; regulatory T cells; Survival Rate; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - immunology; TGF‐β; Transforming Growth Factor beta - antagonists & inhibitors; Tumor Cells, Cultured; tumor immunotherapy; Tumors; Antineoplastic agent; Peptides; Transforming growth factor β; Treatment efficiency; tumor immunotherapy; regulatory T cells; Cancerology; Treatment; Immunotherapy; T-Lymphocyte; inhibitor peptides; Tumor; TGF-β; Inhibitor; Regulatory cell
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24656

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