IFN α gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment

Abstract

Colorectal cancer ( CRC ) metastatic dissemination to the liver is one of the most life‐threatening malignancies in humans and represents the leading cause of CRC ‐related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune‐competent mice in which TEM s—a subset of Tie2 + monocytes/macrophages found at peritumoral sites—express interferon‐alpha ( IFN α), a pleiotropic cytokine with anti‐tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEM s accumulate in the proximity of hepatic metastatic areas and that TEM ‐mediated delivery of IFN α inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFN α does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio‐resistant hepatic microenvironment. TEM ‐mediated IFN α expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEM s were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site‐specific drug‐delivery strategies in patients with  CRC . image Despite recent improvements in the treatment of CRC , a significant number of patients still succumb to CRC metastatic disease, especially of the liver. This study suggests that targeted IFN α gene/cell therapy of hepatic lesions may improve therapeutic outcomes. In preclinical CRC liver metastasis mouse models, Tie2 + monocytes/macrophages ( TEM s) accumulate in the proximity of hepatic lesions; TEM ‐mediated delivery of IFN α inhibits tumor growth and improves overall survival. By acting on the radio‐resistant hepatic microenvironment, IFN α primarily limits the early phases of hepatic CRC cell expansion. Further containment of cancer growth may result from IFN α‐induced anti‐tumor immune responses. Targeted gene/cell therapy of IFN α causes neither detectable side effects nor hematopoietic toxicity and does not inhibit the host response to a virus challenge. TEM s localize near human CRC liver metastases, suggesting that that this targeted gene/cell therapy approach could be employed as an additional adjuvant therapy for patients with, or at high risk of developing, CRC liver metastases.