Humanized PD-1 Knock-in Mice Reveal Nivolumab’s Inhibitory Effects on Glioblastoma Tumor ProgressionIn Vivo

Abstract

Background/Aim: Immunotherapy has been considered a promising approach for brain tumor treatment since the discovery of the brain lymphatic system. Glioblastoma (GBM), the most aggressive type of brain tumor, is associated with poor prognosis and a lack of effective treatment options. Materials and Methods: To test the efficacy of human anti-PD-1, we used a humanized PD-1 knock-in mouse to establish an orthotopic GBM-bearing model. Results: Nivolumab, a human anti-PD-1, effectively inhibited tumor growth, increased the survival rate of mice, enhanced the accumulation and function of cytotoxic T cells, reduced the accumulation and function of immunosuppressive cells and their related factors, and did not induce tissue damage or biochemical changes. The treatment also induced the accumulation and activation of CD8 + cytotoxic T cells, while reducing the accumulation and activation of myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages in the immune microenvironment. Conclusion:Nivolumab has the potential to be a treatment for GBM.Glioblastoma (GBM) is a prevalent malignant tumor of the central nervous system that frequently occurs in both adults and children. Despite the benefits of resection, radiotherapy, and temozolomide chemotherapy in improving the prognosis, glioblastoma patients continue to face a significant mortality risk. The improvement of prognosis in glioblastoma is a critical area of research that necessitates the development of effective innovative approaches (1-3).Vascular endothelial growth factor (VEGF) is an angiogenic protein required for tumor progression. Glioblastoma employs the expression of VEGF to induce angiogenesis and increase blood-brain barrier (BBB) permeability. Consequently, this process results in the development of peritumoral edema (4, 5). Tumor-associated edema is frequently treated with corticosteroid therapy (6). Bevacizumab is a humanized anti-VEGF monoclonal antibody that was approved by the FDA in 2009 for the treatment of recurrent glioblastoma. By targeting the VEGF pathway, it does not only inhibit angiogenesis but also alleviates BBB permeability and peritumoral edema (4,7,8).The synergy between the innate and adaptive immune systems is crucial for achieving antitumor immunity, which involves the combined action of both immune responses to effectively suppress tumors (9). CD8 + T cells, also known as cytotoxic T lymphocytes (CTLs), play a vital role in the immune response against tumors by eliminating tumor cells 1991