Innovative PBMC-derived humanized mouse model reveals CD8+ T cell-intrinsic regulation during antitumor immunity

The PBMC-derived humanized mouse model (PBMC model) may serve as an excellent tool in the field of immunology for both preclinical research and personalized therapeutic strategy development. However, single transplantation of complete PBMCs without modifications prevents the identification of cell type-specific factors that are potentially involved in modulating cell-intrinsic functions for the immune response. Here, we establish an innovative strategy for PBMC model generation, where two-step transplantations coupled with cell type-specific gene manipulation were conducted to evaluate the potential role of CD8⁺ T cell-intrinsic factors in regulating antitumor immunity toward PDX-based tumors. This method readily yields over 10 % of human CD45⁺ cells within the PBMCs of humanized mice with high editing efficiency of gene expression in CD8⁺ T cells that can be subsequently detected in the tumor microenvironment (TME). Our work provides a new method to generate a PBMC-derived humanized mouse model for investigating regulators of interest during antitumor immunity in a cell type-specific manner.