title: Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma.
abstract: We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL-12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy.
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.|CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Malvicini
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Esteban
authors.initials: E
authors.lastname: Fiore
authors.affiliation: Dipartamento di Sanità Pubblica, Medicina Clinica e Moleculare, Università degli studi di Cagliari, Sardegna, Italia.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ghiaccio
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Flavia
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Miguel
authors.initials: M
authors.lastname: Rizzo
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Lucila
authors.initials: L
authors.lastname: Olmedo Bonadeo
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.|CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: García
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rodríguez
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Bayo
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.
authors.forename: Estanislao
authors.initials: E
authors.lastname: Peixoto
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.|CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: Catalina
authors.initials: C
authors.lastname: Atorrasagasti
authors.affiliation: CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.|CIT NOBA, Universidad Nacional del Noroeste, Junín, Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Alaniz
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.|CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aquino
authors.affiliation: CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.|Institute of Experimental Genetics, School of Medical Sciences, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Matar
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Universidad Austral, Buenos Aires, Argentina.|CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006923:Hymecromone / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018664:Interleukin-12; D006923:Hymecromone; D003520:Cyclophosphamide