TMIC-38 - CD39 expression in glioblastoma tumor microenvironment does not affect survival or T-cell exhaustion

Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months. GBM is very difficult to treat due to numerous factors, including the paucity of immune infiltration of the tumor itself. Efforts to overcome this have led to use of immune checkpoint inhibitors such as PD-1 inhibitor, which have revolutionized treatment of many other solid tumors, and yet have not been successful in the treatment of GBM. This has led to many studies investigating various other similar markers. One such marker is CD39, which is highly upregulated in GBM and functions as the first enzyme in the metabolic pathway of ATP breakdown to adenosine. Additionally, CD39 is thought to contribute to T-cell exhaustion. Like PD-1, CD39 inhibition has had preliminary success in the treatment of other solid tumors. However, when tested on GBM, blocking the ATP breakdown pathway did not improve survival in mice, even in conjunction with PD-1 inhibition. Our team sought to determine if the expression of CD39 on the cell surface functioned as an exhaustion marker by injecting two different cell lines of GBM into CD39 global null mice. There was no survival benefit seen in either cell line when compared to wild type mice. Next, expression of known exhaustion markers such as PD-1, TIM3, and LAG3 on tumor infiltrating lymphocytes were analyzed. Expression of TIM3 and 2B4 were found to be increased in CD39KO mice in comparison to wild type (p < 0.01). Additionally, numerous exhaustion markers such as LAG3, TIGIT, and CTLA4 were decreased on tumor in comparison to peripheral blood (p < 0.01). These results demonstrate the complex nature of immune signaling in GBM tumor microenvironment that our team continues to investigate.