Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development

Abstract

Glioblastoma is the most common brain malignant tumor in the adult population, and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. The goal of immunotherapy is to promote tumor eradication, boost the patient’s innate and adaptive immune responses, and overcome tumor immune resistance. A range of new, promising immunotherapeutic strategies has been applied for glioblastoma, including vaccines, oncolytic viruses, immune checkpoint inhibitors, and adoptive cell transfer. However, the main challenges of immunotherapy for glioblastoma are the intracranial location and heterogeneity of the tumor as well as the unique, immunosuppressive tumor microenvironment. Owing to the lack of appropriate tumor models, there are discrepancies in the efficiency of various immunotherapeutic strategies between preclinical studies (with in vitro and animal models) on the one hand and clinical studies (on humans) on the other hand. In this review, we summarize the glioblastoma characteristics that drive tolerance to immunotherapy, the currently used immunotherapeutic approaches against glioblastoma, and the most suitable tumor models to mimic conditions in glioblastoma patients. These models are improving and can more precisely predict patients’ responses to immunotherapeutic treatments, either alone or in combination with standard treatment.

Identification of an IFN-β-associated gene signature for the prediction of overall survival among glioblastoma patients

“…Brain glioblastoma multiforme (GBM) is the most common primary malignant intracranial tumor (50%), and is associated with high morbidity and mortality in both adults and children (1)(2)(3)(4). A histopathological from low-grade to high-grade transformation is associated with poor overall survival (5).…”

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

“…Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of Tregs, which are T cell surface glycoprotein CD4 positive (CD4 + ), interleukin-2 receptor subunit alpha positive (CD25 + ), and forkhead box protein P3 positive (scurfin) cells. The recruitment of immune cells, such as (tumor-infiltrating) lymphocyte (TIL), the myeloidderived suppressor cells (MDSCs), (tumor-infiltrating) monocytes-macrophages (TAMs), innate lymphoid cells (ILCs), regulatory T cells (Tregs) [122], multipotent MSCs, immature dendritic cells (DCs), and NK cells [52] contribute to tumor-induced immunosuppression [123].…”

“…Prolonged survival appears to require combined treatments [ 49 ]. Immunotherapies [ 50 ] are increasingly replaced by CAR-T [ 51 ] and potentially NK cell-targeted therapies [ 52 , 53 ]. Other approaches target tumor metabolism, such as IDH inhibitors in IDH mutated astrocytoma [ 9 ].…”

“…In cancer, chemoattractions among cancer and immune cells are, to a large extent, mediated by chemokines and their receptors [ 52 , 78 ]. In GBM, the receptors CXCL12, CXCR4, and CXCR7 maintain the interaction between endothelial cells and GBM, promoting angiogenesis and homing GSCs to their perivascular niches [ 34 , 85 , 86 ].…”

Molecular and Cellular Mechanisms of Glioblastoma

“…The six reviews touch on interesting topics, such as immunotherapy [1,2], extracellular vesicles [3], energy metabolism [4], translational machinery [5] and the Hippo signaling pathway [6] in glioblastoma.…”