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

• Published in: Cancer cell Vol. 41; no. 11; pp. 1892 - 1910.e10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 13.11.2023
• Subjects: 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); EOMES; Type 1 regulatory T cells (Tr1); Liver metastases; Interferon-alpha; Tumor-associated macrophages (TAMs); Immunotherapy; Pancreatic cancer; Interleukin-10 (IL-10); Gene therapy; Colorectal cancer (CRC)
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.09.014

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. [Display omitted] •IFNα from in vivo LV-engineered liver macrophages curbs liver metastasis growth•IFNα activates antigen presentation and CD8+ T cell effector function•Resistance to IFNα is associated with Eomes CD4+ T cells, IL-10 signaling, and CTLA-4•IFNα combined with anti-CTLA-4 bypasses resistance attaining complete response In this study, Kerzel et al. describe a lentiviral vector platform to selectively engineer liver macrophages to deliver IFNα to liver metastases from within the tissue achieving therapeutic efficacy. Simultaneous combination with anti-CTLA-4 bypassed resistance mechanisms and expanded tumor-reactive T cells, attaining complete response in most mice.