Open AccessReversal of gastrointestinal carcinoma‐induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL‐12
Author(s) -
Malvicini Mariana,
Ingolotti Mariana,
Piccioni Flavia,
Garcia Mariana,
Bayo Juan,
Atorrasagasti Catalina,
Alaniz Laura,
Aquino Jorge B.,
Espinoza Jaime A.,
Gidekel Manuel,
Scharovsky O. Graciela,
Matar Pablo,
Mazzolini Guillermo
Publication year - 2011
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2011.03.007
Subject(s) - medicine , immunotherapy , cancer research , immunosuppression , adoptive cell transfer , spleen , cyclophosphamide , immune system , immunology , population , myeloid derived suppressor cell , cytotoxic t cell , combination therapy , cancer , t cell , pharmacology , chemotherapy , in vitro , biology , suppressor , biochemistry , environmental health
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.