Precision modeling of tumor antigen-specific T-cell responses in humanized mice for preclinical assessment of cancer immunotherapies.

backgroundHumanized mice are highly valuable models for the preclinical development of cancer immunotherapies. However, conventional models often fail to mount robust and trackable tumor antigen-specific (TA-specific) T-cell responses, which hinders the comprehensive evaluation of therapies that depend on this endogenous antitumor immunity.

methodsTo address this limitation, we generated a humanized mouse model by engrafting immunodeficient mice with human hematopoietic stem cells that were transduced with predefined T-cell receptor (TCR) specificities. This approach enables the de novo generation of naïve, functional TA-specific T cells at adjustable frequencies.

resultsWe found that transgene-bearing human thymocytes have a developmental advantage in the murine thymus, likely due to the early formation of the transgenic TCR and associated autonomous signaling. In tumor studies, the presence of these TA-specific T cells delayed tumor growth and promoted increased phenotypic diversity of intratumoral T cells, including the formation of PD-1

conclusionsThis adaptable and physiologically relevant model provides a platform to dissect the complex interplay between human tumors, immune cells, and immunotherapies and has the potential to significantly improve the translation of preclinical findings to the clinic.