A novel immunocytokine promotes T cell– and cytokine-induced killer cell-mediated antitumor immunity via a non-MHC-restricted mechanism in glioblastoma
Year: 2025
Type: article
Abstract: BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by an immunosuppressive microenvironment. To address the immune desert in GBM, immunocytokine, an innovative recombinant fusion protein that combines antibodies and cytokines, has been proposed. This molecule, targeting tumor cells while stimulating immune cells, effectively enhances the anti-tumor response. Developing a novel immunocytokine presents a promising strategy for GBM. METHODS: In this study, we developed a novel immunocytokine, αBC-IL15, composed of a bispecific T cell engager (BsTCE) fused to the interleukin-15 receptor alpha-sushi domain/interleukin-15 complex (IL-15/IL-15Rα). To analyze its affection on immune cells, we co-cultured it with peripheral blood mononuclear cells in vitro. To investigate whether it enhances the cytotoxicity of T cells compared to B7-H3 BsTCE, we performed cytotoxicity assays on cell lines and spheroids in vitro. Moreover, we assessed its efficacy in vivo and analyzed the tumor microenvironment using flow cytometry and bulk sequencing. RESULTS: Our study assessed the bioactivity and efficiency of αBC-IL15. In vitro, αBC-IL15 effectively bound to tumor cells and T cells, inducing immune cell activation, cytokine release, and cytotoxicity toward tumor cells. In vivo, αBC-IL15 connects cytotoxic immune cells with tumor cells, leading to effective immune cell infiltration and potent redirected lysis. CONCLUSIONS: Overall, we developed a novel bispecific immunocytokine, αBC-IL15, which targets tumor cells while enriching and activating effector immune cells. This agent significantly enhanced anti-tumor effects both in vitro and in vivo, highlighting its potential to overcome the immunosuppressive microenvironment in GBM.
Authors: Xiaoke Zhang, Nian Yang, Xin Tang, Nanxi Liu, Qizhong Lu, Zongliang Zhang, Long Xu, Lu Jiang, Honglin Ge, Huaqing Lu, Yongdong Chen, Mingbin Bao, Aiping Tong, Liangxue Zhou
Institutions: Sichuan University, West China Medical Center of Sichuan University, West China Hospital of Sichuan University, Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Biotherapy, University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Mianyang Central Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
Awards: G1263850406, G1993268991
OpenAlex ID: W4416997959