In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases.
Cancer Cell
; 41(11): 1892-1910.e10, 2023 11 13.
Article
in En
| MEDLINE
| ID: mdl-37863068
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
CD8-Positive T-Lymphocytes
/
Liver Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2023
Document type:
Article
Affiliation country:
Italy