Peptide inhibitors of transforming growth factor-beta enhance the efficacy of antitumor immunotherapy.
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.
Llopiz
Diana
D
Division of Hepatology and Gene Therapy, University of Navarra, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Dotor
Javier
J
Casares
Noelia
N
Bezunartea
Jaione
J
Díaz-Valdés
Nancy
N
Ruiz
Marta
M
Aranda
Fernando
F
Berraondo
Pedro
P
Prieto
Jesús
J
Lasarte
Juan José
JJ
Borrás-Cuesta
Francisco
F
Sarobe
Pablo
P
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology*; D011070:Poly I-C / Q000276:immunology / Q000627:therapeutic use; D018125:Receptors, Transforming Growth Factor beta; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; C504795:TGF-beta1 type III receptor (730-743), human; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein; D010047:Ovalbumin; D011070:Poly I-C