In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases
Thomas Kerzel, Giovanna Giacca, Stefano Beretta, Chiara Bresesti, Marco Notaro, Giulia Maria Scotti, Chiara Balestrieri, Tamara Canu, Miriam Redegalli, Federica Pedica, Marco Genua, Renato Ostuni, Anna Kajaste‐Rudnitski, Masanobu Oshima, Giovanni Tonon, Ivan Merelli, Luca Aldrighetti, Paolo Dellabona, Nadia Coltella, Claudio Doglioni, Paola M. V. Rancoita, Francesca Sanvito, Luigi Naldini, Mario Leonardo Squadrito
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.