Abstract B48: PI3Kδ-specific inhibitors may act as adjuvants in the immunotherapy of glioblastoma

Abstract

Abstract Glioblastoma is the most devastating form of primary brain tumor. Despite surgery, radiotherapy, and concomitant temozolomide chemotherapy, the survival rate remains disappointing. Multiple factors including a diverse array of signaling pathways play significant roles in glioblastoma pathogenesis. Of note, the phosphoinositide 3-kinase (PI3K) signaling pathway is often aberrant in glioblastoma, leading to uncontrolled cell proliferation, migration, and invasion into nearby normal brain tissues. The PI3Kδ isoform, predominantly found in leukocytes, is expressed in a number of tumors including glioblastoma. We had previously shown that PI3Kδ is also expressed in glioma cells such as the U87-MG cell line. Using siRNA knockdown technique, we demonstrated that it is important in glioma cell migration and invasion. Interestingly, its expression has been reported to associate with glioma cell resistance to erlotinib. To further study the mechanistic role of PI3Kδ in glioma pathogenesis, we created two knockout cell strains of U87-MG by CRISPR-Cas9 technology. We performed global transcriptome and pathway analysis comparing the parent cell line U87-MG with these knockout cell strains. Our results showed that the mRNA expression of Pleckstrin 2 (PLEK2) is dramatically reduced in PI3Kδ knockout cells. This is confirmed by quantitative RT-PCR. Western blot analysis showed that PLEK2 protein level is reduced by more than 90% and the phosphorylation of Akt at 308, but not 473, is also reduced. PLEK2 contributes to lamellipodia formation and cell spreading via actin cytoskeleton rearrangement, ultimately affecting cell migration and invasion. Our recent findings further strengthen the important role of PI3Kδ in glioma cell motility. It has been shown recently that inhibition of PI3Kα/δ directly enhances effector CD8+ T-cell activity. Thus, use of PI3Kδ-specific inhibitors may reduce expression of PLEK2 thereby reduces glioma cell migration and at the same time promotes antitumor immunity. PI3Kδ inhibitors may also be used as adjuvants together with immune checkpoint inhibitors such as pembrolizumab to prolong the survival of glioblastoma patients. Citation Format: Zulfikar Azam, Shao Wei, Tony To. PI3Kδ-specific inhibitors may act as adjuvants in the immunotherapy of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B48.