Precision modeling of tumor antigen-specific T-cell responses in humanized mice for preclinical assessment of cancer immunotherapies - PubMed
4 hours ago
- #Cancer Immunotherapy
- #T-cell Response
- #Humanized Mouse Model
- A humanized mouse model was created by engrafting mice with human hematopoietic stem cells transduced with predefined T-cell receptor specificities to generate naive, functional tumor antigen-specific T cells at adjustable frequencies.
- Transgene-bearing human thymocytes showed a developmental advantage in the murine thymus due to early transgenic TCR formation and autonomous signaling, which delayed tumor growth and increased phenotypic diversity of intratumoral T cells, including PD-1+/TCF1+ precursor exhausted T cells.
- The model demonstrated that high baseline frequencies of tumor antigen-specific T cells reduced the efficacy of a T-cell bispecific antibody, indicating pre-existing exhaustion limits its activity, and costimulatory agonists (FAP-CD40 and FAP-4-1BBL) depended on this T-cell compartment for antitumor efficacy.
- This adaptable and physiologically relevant model provides a platform to study interactions between human tumors, immune cells, and immunotherapies, potentially improving translation of preclinical findings to clinical applications.