IMPS-42CD70—A KEY DRIVER OF CHEMOKINE-MEDIATED IMMUNE SUPPRESSION AND INDICATOR OF NEGATIVE PROGNOSIS FOR GLIOBLASTOMA

Identifying factors that contribute to the aggressiveness of glioblastoma (GBM) is crucial for treating this deadly brain tumor. We demonstrate here that CD70, a member of the TNF family, is overexpressed by tumor cells in a subset of patients with low grade glioma and GBM. The elevated gene and protein expression is associated with increased tumor grade and recurrences. CD70 expression on primary GBM is correlated with T cells infiltration and tumor MHC class I expression which could potentially promote antitumor immunity based on our result that T cell infiltration is negatively associated with GBM proliferation. However, no correlation between T cell infiltration and prolonged survival is seen, suggesting that other factors may exist to suppress T cell function. Analysis from 155 primary GBM patients using RNA-seq data culled from TCGA indicates that the gene expression of CD70 is highly correlated with markers (CD4, CD25, CD163 and CD14) commonly expressed on immune suppressive cells such as Tregs and tumor associate macrophages. This result is in line with additional finding that CD70 positive tumors display a predominantly mesenchymal gene expression signature, a subtype of GBM that has greater infiltration by immune cells than other subtypes. In addition, tumors derived from patients with MGMT promoter un-methylation express high levels of CD70. Furthermore, our results suggest that CD70 is a key driver of chemokine mediated attraction for these immune suppressive cells infiltrating the tumor. Lastly, shorter overall survival was observed in these patients who have high CD70 expression compared to those with low CD70 expression on tumors. Taken together, the data suggest that CD70 plays a critical role in chemokine-mediated immune suppression and in GBM progression. Targeting GBM with a drug-conjugated CD70 antibody or CD70-CAR T-cells may improve the therapeutic efficacy for patients with GBM.