genO-hCCR8/hCCL1 humanized model for efficacy assessment of CCR8/CCL1-targeting therapies

Background

Modulation of tumor microenvironment has shown to be a promising approach to treat cancer. Among diverse mechanisms responsible for tumor immunosuppression, those mediated by regulatory T cells (Treg) infiltrating in tumor are well identified and known to reduce the efficacy of anti-tumor therapies. CCR8 has been identified as a potential therapeutic target due to its role in the immunosuppression induced by Treg. CCL1 is the major CCR8 ligand and CCL1/CCR8 interaction induces STAT3-dependent up-regulation of FoxP3, CD39, IL-10 and Granzyme B, leading to the enhancement of the suppressive activity of Treg cells. A major challenge in the development of new therapeutic approaches relies on the choice of the right preclinical model, which could mimic the complexity of interactions among different cell types and closely predict the effects of therapeutics in humans. The current therapeutic approaches directed toward the CCR8/CCL1 axis target the receptor CCR8, requiring its humanization for assessment of therapeutics displaying species-specific activity. The development of a physiologically relevant model depends, among others, on the maintenance of a proper interaction of the receptor and ligand. Here we describe two humanized models, genO-hCCR8/hCCL1 and genO-BRGSF-HIS suitable for the assessment of efficacy and safety of CCR8-targeting compounds.