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.

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. - In: CANCER CELL. - ISSN 1535-6108. - 41:11(2023), pp. 1892-1910. [10.1016/j.ccell.2023.09.014]

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

Kerzel, Thomas
Co-primo
;
Giacca, Giovanna
Co-primo
;
Beretta, Stefano
Secondo
;
Bresesti, Chiara;Notaro, Marco;Redegalli, Miriam;Pedica, Federica;Ostuni, Renato;Tonon, Giovanni;Aldrighetti, Luca;Doglioni, Claudio;Rancoita, Paola M V
Formal Analysis
;
Naldini, Luigi
Penultimo
;
2023-01-01

Abstract

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.
2023
Colorectal cancer (CRC)
EOMES
Gene therapy
Immunotherapy
Interferon-alpha
Interleukin-10 (IL-10)
Liver metastases
Pancreatic cancer
Tumor-associated macrophages (TAMs)
Type 1 regulatory T cells (Tr1)
Colorectal cancer (CRC)
EOMES
Gene therapy
Immunotherapy
Interferon-alpha
Interleukin-10 (IL-10)
Liver metastases
Pancreatic cancer
Tumor-associated macrophages (TAMs)
Type 1 regulatory T cells (Tr1)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/155196
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