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In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases.
Kerzel, Thomas; Giacca, Giovanna; Beretta, Stefano; Bresesti, Chiara; Notaro, Marco; Scotti, Giulia Maria; Balestrieri, Chiara; Canu, Tamara; Redegalli, Miriam; Pedica, Federica; Genua, Marco; Ostuni, Renato; Kajaste-Rudnitski, Anna; Oshima, Masanobu; Tonon, Giovanni; Merelli, Ivan; Aldrighetti, Luca; Dellabona, Paolo; Coltella, Nadia; Doglioni, Claudio; Rancoita, Paola M V; Sanvito, Francesca; Naldini, Luigi; Squadrito, Mario Leonardo.
Affiliation
  • Kerzel T; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
  • Giacca G; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
  • Beretta S; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Bioinformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Bresesti C; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
  • Notaro M; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
  • Scotti GM; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Balestrieri C; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Canu T; Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Redegalli M; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Pedica F; Vita Salute San Raffaele University, 20132 Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Genua M; Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Ostuni R; Vita Salute San Raffaele University, 20132 Milan, Italy; Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Kajaste-Rudnitski A; Retrovirus-Host Interactions and Innate Immunity to Gene Transfer, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Oshima M; Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
  • Tonon G; Vita Salute San Raffaele University, 20132 Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Merelli I; Bioinformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; National Research Council, Institute for Biomedical Technologies, 20054 Segrate, Italy.
  • Aldrighetti L; Vita Salute San Raffaele University, 20132 Milan, Italy; Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Dellabona P; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Coltella N; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Doglioni C; Vita Salute San Raffaele University, 20132 Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Rancoita PMV; CUSSB University Center for Statistics in the Biomedical Science, Vita Salute San Raffaele University, 20132 Milan, Italy.
  • Sanvito F; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Naldini L; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy. Electronic address: naldini.lugi@hsr.it.
  • Squadrito ML; Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy. Electronic address: squadrito.mario@hsr.it.
Cancer Cell ; 41(11): 1892-1910.e10, 2023 11 13.
Article in En | MEDLINE | ID: mdl-37863068
Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
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Full text: 1 Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Liver Neoplasms Limits: Animals / Humans Language: En Year: 2023 Type: Article

Full text: 1 Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Liver Neoplasms Limits: Animals / Humans Language: En Year: 2023 Type: Article