TMIC-42. ACROLEIN PRODUCED BY GLIOMA CELLS UNDER HYPOXIA INHIBITS NEUTROPHIL AKT ACTIVITY AND SUPPRESSES ANTI-TUMORAL ACTIVITIES

Abstract Glioblastoma (GBM), WHO grade 4 glioma, is the most malignant primary brain tumor. The median overall survival of GBM ranges from 12 to 16 months. The tumor microenvironment of GBM is characterized by tissue hypoxia and infiltration of immunosuppressive cells. Neutrophils have been reported to shift from an anti-inflammatory phenotype to a pro-tumoral role (N2 phenotype) during glioma progression. However, the mechanism of this transformation remains unclear. Acrolein (Acr) is a highly-reactive α,β-unsaturated aldehyde produced under hypoxic conditions via lipid peroxidation, resulting in cellular impairment through DNA or protein conjugation. In this study, we found that acrolein produced by U87MG cells under hypoxic conditions suppresses neutrophil superoxide generation, inhibits neutrophil tumor-suppressive activities, and induces N2 marker arginase 1 (Arg-1) expression. Scavenging acrolein with dimercaprol reverses these effects. Further investigation revealed that acrolein inhibits AKT enzymatic activity by forming Acr-AKT conjugates at Cys 310. In a syngeneic subcutaneous mice glioma model, dimercaprol treatment is associated with decreased tumor size, reduced acrolein conjugate expression in the tumor tissue, and restored neutrophil superoxide generation. In addition, we also found that the higher acrolein-DNA adduct expression in tumor tissues is associated with a poor prognosis of glioma patients, and the evaluated acrolein-protein conjugates in the serum of glioma patients are correlated to the functional impairment of neutrophils. These results suggest acrolein polarizes the neutrophils toward the N2 phenotype and contributes to the immunosuppressive microenvironment and glioma progression. Acrolein scavenging may be a novel strategy for glioma treatment.