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Determining the Role of TOX in the Maintenance of CD8+ T cell Exhaustion and Memory Development

Award Number: F31CA305882
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Determining the Role of TOX in the Maintenance of CD8+ T cell Exhaustion and Memory Development - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	1	6/23/2026	NEW	$0
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	1	6/23/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Determining the Role of TOX in the Maintenance of CD8+ T cell Exhaustion and Memory Development

Award Number: F31CA305882

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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