Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12

Autores
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
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Ingolotti, Mariana. Universidad Austral; Argentina
Fil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: García, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Espinoza, Jaime A.. Universidad Adolfo Ibañez; Chile. Universidad de La Frontera; Chile
Fil: Gidekel, Manuel. Universidad Adolfo Ibañez; Chile
Fil: Scharovsky, Olga Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Fil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Materia
CYCLOPHOSPHAMIDE
GASTROINTESTINAL CARCINOMA
IL-12
IMMUNOSUPPRESSION
TREGS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/79592
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79592
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12Malvicini, MarianaIngolotti, MarianaPiccioni, Flavia ValeriaGarcía, Mariana GabrielaBayo Fina, Juan MiguelAtorrasagasti, María CatalinaAlaniz, Laura DanielaAquino, Jorge BenjaminEspinoza, Jaime A.Gidekel, ManuelScharovsky, Olga GracielaMatar, PabloMazzolini Rizzo, Guillermo DanielCYCLOPHOSPHAMIDEGASTROINTESTINAL CARCINOMAIL-12IMMUNOSUPPRESSIONTREGShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Immunotherapy-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.Fil: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Ingolotti, Mariana. Universidad Austral; ArgentinaFil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: García, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Espinoza, Jaime A.. Universidad Adolfo Ibañez; Chile. Universidad de La Frontera; ChileFil: Gidekel, Manuel. Universidad Adolfo Ibañez; ChileFil: Scharovsky, Olga Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaElsevier2011-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79592Malvicini, Mariana; Ingolotti, Mariana; Piccioni, Flavia Valeria; García, Mariana Gabriela; Bayo Fina, Juan Miguel; et al.; Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12; Elsevier; Molecular Oncology; 5; 3; 6-2011; 242-2551574-7891CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.molonc.2011.03.007info:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/full/10.1016/j.molonc.2011.03.007info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:18:48Zoai:ri.conicet.gov.ar:11336/79592instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:18:48.62CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
title Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
spellingShingle Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
Malvicini, Mariana
CYCLOPHOSPHAMIDE
GASTROINTESTINAL CARCINOMA
IL-12
IMMUNOSUPPRESSION
TREGS
title_short Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
title_full Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
title_fullStr Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
title_full_unstemmed Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
title_sort Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12
dc.creator.none.fl_str_mv 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
author Malvicini, Mariana
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CYCLOPHOSPHAMIDE
GASTROINTESTINAL CARCINOMA
IL-12
IMMUNOSUPPRESSION
TREGS
topic CYCLOPHOSPHAMIDE
GASTROINTESTINAL CARCINOMA
IL-12
IMMUNOSUPPRESSION
TREGS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Ingolotti, Mariana. Universidad Austral; Argentina
Fil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: García, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
Fil: Espinoza, Jaime A.. Universidad Adolfo Ibañez; Chile. Universidad de La Frontera; Chile
Fil: Gidekel, Manuel. Universidad Adolfo Ibañez; Chile
Fil: Scharovsky, Olga Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Fil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina
description 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.
publishDate 2011
dc.date.none.fl_str_mv 2011-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/79592
Malvicini, Mariana; Ingolotti, Mariana; Piccioni, Flavia Valeria; García, Mariana Gabriela; Bayo Fina, Juan Miguel; et al.; Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12; Elsevier; Molecular Oncology; 5; 3; 6-2011; 242-255
1574-7891
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79592
identifier_str_mv Malvicini, Mariana; Ingolotti, Mariana; Piccioni, Flavia Valeria; García, Mariana Gabriela; Bayo Fina, Juan Miguel; et al.; Reversal of gastrointestinal carcinoma-induced immunosuppression and induction of antitumoural immunity by a combination of cyclophosphamide and gene transfer of IL-12; Elsevier; Molecular Oncology; 5; 3; 6-2011; 242-255
1574-7891
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molonc.2011.03.007
info:eu-repo/semantics/altIdentifier/url/https://febs.onlinelibrary.wiley.com/doi/full/10.1016/j.molonc.2011.03.007
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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