Understanding the role of TNFR2 signaling in CD8 T cell exhaustion.

Glioblastoma (GBM) is the most common primary brain cancer in adults with a median survival less than 15 months. Approaches harnessing the immune response are hindered by multiple factors, including T cell exhaustion. Exhausted T cells are less capable of limiting tumor progression. As cells progress along the exhaustion pathway, SLAM Family Member 6 (SLAMF6) gets downregulated and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) and TOX are upregulated. TOX is both necessary and sufficient to initiate the terminal exhaustion program. However, our understanding of the pathways that lead to the upregulation of TOX remains incomplete.

We hypothesized that tumor necrosis factor (TNF) could be involved in the upregulation of TOX, as TNF has been shown to induce exhaustion. We observed upregulation of the TNF receptor type II (TNFR2) in tumor-infiltrating T cells, but not in lymphoid organs. Furthermore, TNFR2 expression is correlated with canonical exhaustion markers. Interestingly, TNFR2 knock out (KO) CD8 T cells express TIM3 but exhibit significantly less TOX. These data suggest that TIM3 and TOX are regulated independently. Finally, TNFR2 KO mice have significantly better CD8-mediated tumor control against subcutaneous GBM tumors. Further studies will need to be performed to determine whether TNFR2 expression on CD8 T cells is sufficient to mediate this anti-tumor effect and whether TNFR2 blockade could improve the efficacy of current treatments.