In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases [scRNA-seq TCR]
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 (IFNa) to liver metastases. Gene-based IFNa delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNa 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 IFNa 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. Overall design: Single-cell transcriptomics with corresponding TCRs (VDJ) on metastatic liver in three distinct cohorts: (1) Control: Control LV-treated mice, (2) IFNa: IFNa LV-treated mice and, (3) IFNa + aCTLA4: mice treated with IFNa in combination with a-CTLA-4.