title: IFNα gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment.
abstract: Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life-threatening malignancies in humans and represents the leading cause of CRC-related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune-competent mice in which TEMs-a subset of Tie2(+) monocytes/macrophages found at peritumoral sites-express interferon-alpha (IFNα), a pleiotropic cytokine with anti-tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM-mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNα does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio-resistant hepatic microenvironment. TEM-mediated IFNα expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site-specific drug-delivery strategies in patients with CRC.
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Catarinella
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Monestiroli
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Angiogenesis and Tumor Targeting Research Unit and San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Escobar
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Amleto
authors.initials: A
authors.lastname: Fiocchi
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Ngoc Lan
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Aiolfi
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Marra
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Hepatopancreatobiliary Surgery Unit, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cipriani
authors.affiliation: Hepatopancreatobiliary Surgery Unit, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Aldrighetti
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy Angiogenesis and Tumor Targeting Research Unit and San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases IRCCS San Raffaele Scientific Institute, Milan, Italy sitia.giovanni@hsr.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000150:complications* / Q000517:prevention & control / Q000628:therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000628:therapy*; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control* / Q000628:therapy; D016019:Survival Analysis
chemical_list: D016898:Interferon-alpha
keywords: colorectal cancer; gene therapy; interferon‐alpha; liver metastases; tumor microenvironment