In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases.

Autor:	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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2023 Nov 13; Vol. 41 (11), pp. 1892-1910.e10. Date of Electronic Publication: 2023 Oct 19.
DOI:	10.1016/j.ccell.2023.09.014
Abstrakt:	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. Competing Interests: Declaration of interests L.N., M.L.S., and T.K. are inventors on a patent on KC-directed gene transfer and L.N. is an inventor on patents on miRNA-regulated LV technology filed and managed by the San Raffaele Scientific Institute and the Telethon Foundation. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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