Authors: Malvicini, Mariana; Ingolotti, Mariana; Piccioni, Flavia Valeria; García, Mariana Gabriela; Bayo Fina, Juan Miguel; Atorrasagasti, María Catalina; Alaniz, Laura Daniela; Aquino, Jorge Benjamin; Espinoza, Jaime A.; Gidekel, Manuel; Scharovsky, Olga Graciela; Matar, Pablo; Mazzolini Rizzo, Guillermo Daniel
Publication Date: 2011.
Language: English.
Abstract:
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 + AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-β 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-γ-secreting CD4+ T cells able to eradicate established CRC tumours after adoptive transfer. Finally, we evaluated the combination on disseminated CRC and pancreatic carcinoma (PC). Cy + 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 + AdIL-12 might be a valid immunotherapeutic strategy for advanced GIC.
Author affiliation: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Ingolotti, Mariana. Universidad Austral; Argentina
Author affiliation: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: García, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Author affiliation: Espinoza, Jaime A.. Universidad Adolfo Ibañez; Chile. Universidad de La Frontera; Chile
Author affiliation: Gidekel, Manuel. Universidad Adolfo Ibañez; Chile
Author affiliation: Scharovsky, Olga Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Author affiliation: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Author affiliation: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas