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

被引:54
作者
Llopiz, Diana [1 ]
Dotor, Javier [2 ]
Casares, Noelia [1 ]
Bezunartea, Jaione [1 ]
Diaz-Valdes, Nancy [1 ]
Ruiz, Marta [1 ]
Aranda, Fernando [1 ]
Berraondo, Pedro [1 ]
Prieto, Jesus [1 ]
Jose Lasarte, Juan [1 ]
Borras-Cuesta, Francisco [1 ]
Sarobe, Pablo [1 ]
机构
[1] Univ Navarra, Ctr Appl Med Res CIMA, Div Hepatol & Gene Therapy, Pamplona 31008, Spain
[2] Digna Biotech, Madrid, Spain
关键词
regulatory T cells; TGF-beta; inhibitor peptides; tumor immunotherapy; REGULATORY T-CELLS; TGF-BETA; SUPPRESSOR-CELLS; IN-VIVO; IMMUNE-RESPONSE; TUMOR EVASION; LYMPHOCYTES-B; EXPRESSION; CANCER; BIOLOGY;
D O I
10.1002/ijc.24656
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (c) 2009 UICC
引用
收藏
页码:2614 / 2623
页数:10
相关论文
共 48 条
[11]   Cancer vaccines: Between the idea and the reality [J].
Finn, OJ .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (08) :630-641
[12]   Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation [J].
Ghiringhelli, F ;
Puig, PE ;
Roux, S ;
Parcellier, A ;
Schmitt, E ;
Solary, E ;
Kroemer, G ;
Martin, F ;
Chauffert, B ;
Zitvogel, L .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (07) :919-929
[13]   CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner [J].
Ghiringhelli, F ;
Ménard, C ;
Terme, M ;
Flament, C ;
Taieb, J ;
Chaput, N ;
Puig, PE ;
Novault, S ;
Escudier, B ;
Vivier, E ;
Lecesne, A ;
Robert, C ;
Blay, JY ;
Bernard, J ;
Caillat-Zucman, S ;
Freitas, A ;
Tursz, T ;
Wagner-Ballon, O ;
Capron, C ;
Vainchencker, W ;
Martin, F ;
Zitvogel, L .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (08) :1075-1085
[14]   In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-β1 [J].
Gil-Guerrero, Lucia ;
Dotor, Javier ;
Huibregtse, Inge Louise ;
Casares, Noelia ;
Belen Lopez-Vazquez, Ana ;
Rudilla, Francesc ;
Ignacio Riezu-Boj, Jose ;
Lopez-Sagaseta, Jacinto ;
Hermida, Jose ;
Van Deventer, Sander ;
Bezunartea, Jaione ;
Llopiz, Diana ;
Sarobe, Pablo ;
Prieto, Jesus ;
Borras-Cuesta, Francisco ;
Jose Lasarte, Juan .
JOURNAL OF IMMUNOLOGY, 2008, 181 (01) :126-135
[15]  
GOMELLA LG, 1989, CANCER RES, V49, P6972
[16]   Transforming growth factor-β in T-cell biology [J].
Gorelik, L ;
Flavell, RA .
NATURE REVIEWS IMMUNOLOGY, 2002, 2 (01) :46-53
[17]   Cutting edge:: TGF-β signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+ CD25+ T cells [J].
Huber, S ;
Schramm, C ;
Lehr, HA ;
Mann, A ;
Schmitt, S ;
Becker, C ;
Protschka, M ;
Galle, PR ;
Neurath, MF ;
Blessing, M .
JOURNAL OF IMMUNOLOGY, 2004, 173 (11) :6526-6531
[18]  
ITO N, 1991, CANCER RES, V51, P4080
[19]  
KEHRL JH, 1986, J IMMUNOL, V137, P3855
[20]   TRANSFORMING GROWTH-FACTOR-BETA AND NONCYTOPATHIC MECHANISMS OF IMMUNODEFICIENCY IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION [J].
KEKOW, J ;
WACHSMAN, W ;
MCCUTCHAN, JA ;
CRONIN, M ;
CARSON, DA ;
LOTZ, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (21) :8321-8325