INVESTIGADORES
GARCIA Mariana Gabriela
artículos
Título:
Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
Autor/es:
MALVICINI M; INGOLOTTI M; PICCIONI F; GARCÍA MG; BAYO J; ATORRASAGASTI C; ALANIZ L; AQUINO JB; ESPINOZA J; GIDEKEL M; SCHAROVSKY G; MATAR P; MAZZOLINI G
Revista:
MOLECULAR ONCOLOGY
Editorial:
ELSEVIER SCI LTD
Referencias:
Lugar: Amsterdam; Año: 2011 vol. 5 p. 242 - 255
ISSN:
1574-7891
Resumen:
Immunotherapy-based strategies for gastrointestinal carcinomas (GIC) have been exploited so far, but these approaches have to face strong mechanisms of immune escape induced by tumours. We previously demonstrated that sub-therapeutic doses of an adenovirus expressing IL-12 genes (AdIL-12) mediated a potent antitumour effect against subcutaneous (s.c.) colorectal carcinomas (CRC) in mice pre-treated with low doses of cyclophosphamide(Cy). In our study we used this combination to assess its impact on the immunosuppressive microenvironment. In s.c. CRC model we demonstrated that non-responder mice failed to decrease Tregs in tumour, spleen and peripheral blood. Reconstitution of Tregs into tumour-bearing mice treated with combined therapy abolished the antitumoural effect. In addition, Cy þ AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-b and their ability to inhibit dendritic cells activation. Combined treatment decreased the number of myeloid-derived suppressor cells (MDSCs) in comparison to non-treated mice and, interestingly, administration of Tregs restored splenic MDSCs population. Furthermore, combined therapy potently generated specific cytotoxic IFN-g secreting CD4þ T cells able to eradicate established CRC tumours after adoptive transfer. Finally, we evaluated the combination on disseminated CRC and pancreatic carcinoma (PC). Cy þ AdIL-12 were able to eradicate liver metastatic CRC (47%) and PC tumour nodules (40%) and to prolong animal survival. The results of this study support the hypothesis that Cy þ AdIL-12 might be a valid immunotherapeutic strategy for advanced GIC.