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Updated: Sep 18, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Human cDC1 enhance cytotoxic function of CD226+ terminally exhausted tumor-infiltrating lymphocytes
Liam O'Brien1, Irina Buckle2, Ingrid M Leal-Rojas1
1Cancer Immunotherapies Research Group, Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, Australia.
Abstract:
Prevention or reversal of T cell exhaustion is a major objective of cancer immunotherapy. However, few models exist to generate, characterize and modulate exhausted human T cells, particularly within solid tumors in vivo, which likely hampers the discovery and translation of novel therapeutics. In this study we describe a humanized mouse model where functional human CD8+ T cells specific for the tumor antigen NY-ESO-1 develop in vivo from human CD34+ hematopoietic stem cells genetically modified to express a HLA-A *0201-restricted NY-ESO-1 specific T cell receptor (TCR). HLA-A *0201+ NY-ESO-1+ expressing A375 melanoma tumors engrafted in these mice and were refractory to treatment with anti-PD-1 despite being infiltrated with NY-ESO-1 specific T cells. Tumor-Infiltrating Lymphocytes (TIL) upregulated tissue resident memory (TRM) markers CD103 and CD69 along with exhaustion markers PD-1, TIGIT, and CD39 relative to T cells from other organs. Further, TILs failed to secrete cytokines TNF and IFNγ following in vitro stimulation with conventional Type I Dendritic Cells (cDC1), indicative of terminal exhaustion. However, cDC1 stimulation of the terminally exhausted NY-ESO-1 specific TILs led to enhanced tumor killing that was associated with increased CD107a and Granzyme B expression that was restricted to a subset of CD226+ NY-ESO-1 specific TILs. These findings establish a novel platform to investigate T cell exhaustion in human tumors and suggest a role for cDC1 in enhancing terminally exhausted TIL cytotoxic function.
Insights
A new humanized mouse model allows study of exhausted T cells in tumors. Conventional Type I Dendritic Cells (cDC1) enhanced killing by terminally exhausted tumor-infiltrating lymphocytes (TILs).
Area of Science:
- Immunology
- Cancer Biology
- Immunotherapy
Background:
- T cell exhaustion hinders cancer immunotherapy effectiveness.
- Lack of models for studying exhausted human T cells in solid tumors impedes therapeutic development.
Purpose of the Study:
- To establish a humanized mouse model for investigating exhausted human T cells within solid tumors.
- To characterize the function of tumor-infiltrating lymphocytes (TILs) in a humanized melanoma model.
- To explore the potential of conventional Type I Dendritic Cells (cDC1) in overcoming T cell exhaustion.
Main Methods:
- Developed a humanized mouse model using genetically modified human CD34+ hematopoietic stem cells expressing an NY-ESO-1 specific T cell receptor (TCR).
- Engrafted human melanoma tumors (A375) expressing NY-ESO-1 into the humanized mice.
- Analyzed TILs for expression of memory and exhaustion markers (CD103, CD69, PD-1, TIGIT, CD39) and cytokine secretion (TNF, IFNγ) after cDC1 stimulation.
Main Results:
- The humanized model successfully generated NY-ESO-1 specific CD8+ T cells that infiltrated tumors.
- Tumor-infiltrating lymphocytes (TILs) exhibited markers of tissue-resident memory and terminal exhaustion (PD-1, TIGIT, CD39).
- Conventional Type I Dendritic Cells (cDC1) stimulation enhanced tumor killing by terminally exhausted TILs, linked to CD107a and Granzyme B expression in CD226+ TILs.
Conclusions:
- This humanized mouse model provides a novel platform for studying human T cell exhaustion in the tumor microenvironment.
- Conventional Type I Dendritic Cells (cDC1) show potential in enhancing the anti-tumor function of terminally exhausted T cells.
- Findings suggest strategies to modulate cDC1 activity could improve cancer immunotherapy outcomes.
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