772 TOX maintains T cell exhaustion and hinders the development of tumor-specific CD8 + T cell memory
Year: 2026
Type: conference-abstract
Abstract: Background Thymocyte selection-associated high mobility group box protein (TOX) is a critical regulator of the T cell exhaustion (T EX) lineage program, having been shown to be necessary for the formation of CD8+ TEX cells. While TOX is highly expressed in intratumoral CD8+ TEX cells, little is known of its function following the onset of T cell dysfunction and whether continuous TOX expression is necessary to maintain TEX. Furthermore, recent reports indicate that TOX is expressed in memory CD8+ T cells; however, it is currently unclear whether TOX promotes or hinders their anti-tumor immunity. Here, we investigated the development and anti-tumor functionality of TOX-deficient memory CD8+ T cells.Methods To assess the impact of TOX ablation in CD8 + TEX cells specifically, we generated ToxL/L Lag3CreERT2 murine models to enable temporal deletion of Tox in TEX cells, that either express a polyclonal TCR repertoire or a single TCR, pMEL, that is specific for the gp100 B16 melanoma antigen. These CD8+ pMEL T cells were utilized in adoptive transfer experiments to investigate the impact of TOX on cell survival, functionality, and the anti-tumor immune response. To investigate the role of TOX in CD8+ memory T cells, we performed tumor-rechallenge experiments and assessed the development and anti-tumor function of TOX-deficient CD8+ memory T cells.Results Induced deletion of TOX in CD8 + TEX cells significantly decreased cell abundance in tumors, compared to control cells. Further analysis revealed that TOX-deficient CD8+ TEX cells have impaired cell proliferative and survival demonstrated by decreased EdU incorporation and increased cCasp3 expression, respectively. Gene expression profiling revealed a role of TOX in maintaining transcriptomic patterns associated with TEX commitment. Despite the substantial prevalence of cell death following TOX ablation, TOX-deficient CD8+ memory T cells demonstrated enhanced anti-tumor immunity, indicated by significantly decreased tumor growth and increased murine survival upon tumor rechallenge. Furthermore, gp100-tetramer analysis revealed increased clonal expansion of tumor antigen-specific CD8+ T cells in TOX-deficient cells, compared to controls.Conclusions Our studies demonstrate a critical role of TOX in maintaining T cell exhaustion. TOX ablation in committed CD8 + TEX cells resulted in apoptotic-driven loss of TEX cells, altered expression of TEX-associated genes, and decreased cell proliferation. Furthermore, our investigations revealed that TOX hinders the anti-tumor immunity of CD8+ memory T cells, potentially by restricting the proliferative capacity of tumor-specific clonotypes.
Institution: University of Pittsburgh
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225158059