TNFR2 Is a Novel Marker of Exhaustion and TNFR2 Blockade Improves Subcutaneous Tumor Control

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2026-06-06

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2024

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Abstract

CD8+ T cells have potent anti-tumor responses. However, continuous stimulation by tumor cells causes these cells differentiate down an exhaustion pathway. This differentiation negatively impacts CD8+ T cell function and response to immunotherapies. One potential factor that influences the progression along this pathway is tumor necrosis factor (TNF). Using multiple tumor models and a chronic viral infection model, we determined that the TNF receptor (TNFR2) is significantly upregulated in tumor- infiltrating CD8+ T cells and CD8+ T cells in the spleen of virus-infected mice. Furthermore, TNFR2 correlated with other canonical markers of exhaustion. We identified that upregulation of TNFR2 was associated with loss of progenitor-like functions and acquisition of functions resembling terminally exhausted cells. To investigate the role of TNFR2 in this transition, we employed TNFR2 KO mice. While the frequency of the progenitor and terminally exhaustion populations were similar, the exhaustion- associated transcription factor TOX was significantly decreased in TNFR2 KO T cells. We demonstrate that the loss of TNFR2 is sufficient to increase effector functions of CD8+ T cells in tumor-draining lymph nodes, but not in the tumor. Loss of TNFR2 resulted in a CD8-mediated reduction in tumor growth in various subcutaneous tumor models. Finally, treatment with a TNFR2 antagonist in combination with an immune checkpoint inhibitor (aPD1) resulted in decreased tumor growth. Together, these data suggest that TNFR2 is a novel marker of exhaustion and blockade could be utilized as a novel treatment strategy.

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Hoyt-Miggelbrink, Alexandra Marina (2024). TNFR2 Is a Novel Marker of Exhaustion and TNFR2 Blockade Improves Subcutaneous Tumor Control. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/30860.

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