[F31] Determining the Role of TOX in the Maintenance of CD8+ T cell Exhaustion and Memory Development
Ente: National Cancer Institute
Scadenza: 2029-06-30
Importo max: 50.114 EUR
Paese: US
Descrizione
ABSTRACT
T cells are key mediators of anti-tumor function that specifically recognize and react to tumor-
expressing antigens; however, the majority tumor-specific T cells in the tumor microenvironment are
exhausted. This is characterized by loss of effector functions and upregulation of immune-inhibitory
receptors (IRs), which pose a significant barrier to immunotherapy efficacy and patient survival. Recent
efforts have focused on therapeutic targeting of exhausted T cells (TEX) through IR inhibition, although
the molecule and underlying mechanisms required to maintain T cell exhaustion remain unknown.
Thymocyte selection-associated high mobility group box protein (TOX) is the master transcription factor
of the T cell exhaustion lineage program with TOX-mediated regulation of TEX cells verified in tumors
or viral infections. Furthermore, TOX has been shown to be necessary for the formation of TEX cells.
While TOX is highly expressed in TEX cells, little is known of the role of TOX after a T cell has entered
the exhausted state. The primary objective of this proposal is to define the role of TOX in CD8+
TEX cells. Recent reports indicate that TOX has a critical role in determining the formation of memory
CD8+ T cells; however, when in the TEX lineage program that TOX influences memory cell fates is
currently unclear. To assess the impacts of the loss of TOX expression in TEX cells specifically, I have
generated conditional knock-out mice to remove TOX in progenitor or terminally exhausted LAG3+ T
cells, that either express a polyclonal TCR repertoire or a single TCR transgene, pMEL, that is specific
for the gp100 B16 melanoma antigen. These CD8+ pMEL T cells will be utilized in adoptive transfer
experiments to investigate the impact of TOX on cell survival, functionality, and the anti-tumor immune
response. Collectively, these data will define the role of TOX in CD8+ TEX cells and enhance our
understanding of how TOX influences memory T cell development. This proposed work will have broad
implications for how T cells are maintained in an exhausted state and inform the prospect of targeting
TOX, or the genes that TOX regulates, as a potential cancer immunotherapy.
Istituzione: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
PI: Samuel Butler
Progetto: 1F31CA305882-01A1
Settori: National Cancer Institute
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