Abstract 3255: Investigate immune regulation and therapeutic efficacy via regorafenib combined with PD-L1 inhibitor in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is one of the most common aggressive primary brain tumors, with poor survival despite after surgery, radiation treatment, and chemotherapy. Regorafenib, a tyrosine kinase inhibitor used for cancer treatment, was known to effectively inhibit angiogenesis and attenuate the activity of oncogene receptor hormones. Currently, regorafenib has been approved to treat various cancer with significant improvement. Though regorafenib show potential to penetrate blood brain barrier, the role of regorafenib in glioblastoma has not been elucidated. With the finding of central nervous lymphatic system, immune checkpoint inhibitor (programmed cell death protein-1 and its ligand) therapy has ongoing with clinical trial in GBM. The PD-L1 on tumor cells may interact with the PD-1 on T cells, and therefore inhibited the proliferation of T cells proliferate and finally cause the immune escape of tumor. While the therapeutic efficacy of using immune checkpoint inhibitor alone is still not significant enough for GBM; thus, it is necessary to find other suitable drugs for combination. Moreover, patient with low PD-L1 expression may not be able to administrate with anti-PD-L1 therapy. Therefore, identifying suitable combination reagent to regulate PD-L1 expression and to enhance efficacy of anti-PD-L1 therapy is important. Our experiment aims to explore whether regorafenib can increase the transcription of PD-L1 via regulating β-catenin-related signal transduction, and thus enhancing the treatment efficacy of immune checkpoint inhibitor (anti-PD-L1) on GBM. Here, we used GL-261 animal model to prove the regulation of regorafenib combined with anti-PD-L1. According to our data, regorafenib can inhibit the proliferation and induce the apoptosis pattern in GBM cells. Further, regorafenib may induce PD-L1 expression via activating β-catenin-related signaling; and therefore, increasing the targeting efficacy of anti-PD-L1 in GBM. Not only induce PD-L1 expression, regorafenib combined with anti-PD-L1 may also induce the accumulation of active cytotoxicity T lymphocytes (CD8+IFN-γ+) and reduce the accumulation of immunosuppressive cells, such as regulatory T cells (CD11b+Gr-1+) and myeloid-derived suppressor cells (CD4+CD25+FOXP3+). In conclusion, our animal experiments suggested that regorafenib may effectively promote PD-L1 transcription in glioblastoma by up-regulating β-catenin-related signaling, thereby increasing the therapeutic target efficacy and effectiveness of immune checkpoint inhibitors. Citation Format: Dai-Cheng Dong, Yu-Chiang Liu. Investigate immune regulation and therapeutic efficacy via regorafenib combined with PD-L1 inhibitor in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3255.