Introduction

Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system (CNS), reaching an incidence rate of 3.23 per 100,000 in the USA [1]. GBM has an aggressive clinical course, with a median survival of 12–15 months [2]. Despite optimal therapy, only 6.8% of patients survive 5 years from diagnosis [1]. GBM has a high recurrence rate with half of the patients experiencing disease progression within 7.4 months [3]. Short progression-free survival and frequent relapses are due to high biological malignancy of the tumor, defined by cell infiltration far beyond the tumor boundaries seen by neuroimaging or macroscopically during tumor resection.

Recently, glioblastoma stem cells (GCS) have arisen as the main source of glioblastoma self-renewal ability, which predetermines its recurrence after resection or radio/chemotherapy. GSCs are located in specific regions of the tumor microenvironment (TME). While there is no clear consensus regarding the subdivision of TME compartments, TME is generally divided into perivascular, perinecrotic/hypoxic, and immune niches [4]. Most stem cells are located in hypoxic and perinecrotic niches of GBM, which are characterized by the imbalance between rapid cancer cells growth and sluggish blood flow [5]. This specific arrangement of GSCs has several clinical implications [5]. Firstly, insufficient blood supply impairs the penetration of chemotherapeutics and facilitates GSCs survival, playing a key role in GBM relapse [5]. Secondly, hypoxic conditions in these two niches promote various adaptive mechanisms within stem cells that contribute to the development of tumor radioresistance [6].

The crosstalk between tumor and stromal cells is regulated by a complicated cytokine network driving local inflammation and immunosuppression [7]. Recently, the family of interleukins has gained attention as the key driver of disease progression. Interleukins modulate the development and differentiation of various immune cells, affecting the non-specific immune response by recruiting neutrophils or activating macrophages [8].

Among them, interleukin 17 (IL-17), a proinflammatory cytokine secreted primarily by T helper 17 (Th17) lymphocytes, emerged as a major regulator of glioblastoma cells proliferation and migration [9]. There are two main mechanisms in which IL-17 drives tumor cell development. Through direct binding with its receptor, IL-17 activates numerous transcription factors, protein kinases, metalloproteinases, and anti-apoptotic proteins, directly stimulating tumor cells [10,11,12]. Indirectly, IL-17 induces the immunosuppressive TME and inhibits the anticancer immune response [13, 14]. IL-17 upregulates the expression of transcription factors such as B-lymphoma Mo-MLV insertion region 1 (BMI1) in GBM cells [15]. BMI1 maintains the self-renewal capacity of GSC, and its overexpression stimulates their proliferation [104,105,106]. The results suggest that combining anti-IL17 agents and immunotherapy is a promising approach to GBM therapy (Table 2); therefore, we expect more research in this area.

Table 2 Summary of preclinical studies targeting IL-17 in GBM
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The role of exosome-based immunotherapy and theranostics and their association with IL-17 in GBM

Currently, we notice a rapidly growing interest in exosomes among scientists including cancer researchers. Exosomes are small extracellular vesicles released by various types of cells, which take part in the transmission of biological signals between cells through nucleic acids such as RNA and proteins. Exosomes are present in many extracellular fluids including blood, urine, saliva, and CSF [107]. Exosomes are released by various immune cells including T lymphocytes, NK cells, and macrophages. Exosomes exhibit immunomodulatory activity and regulate the immune response of the host [107].

To date, the potential applications of exosomes have been demonstrated in the diagnosis, prognosis, and treatment of many diseases including brain tumors. In GBM, exosome-based techniques, such as liquid biopsy, offer rapid, repeatable, and non-invasive/less invasive diagnostic methods. Certain tumor cell-derived exosomes may be prognostic biomarkers in GBM [108]. Exosome-based therapeutics also appear as a promising treatment approach in glioblastoma. For example, exosome-based methods may improve drug penetration through BBB and other biological barriers. Furthermore, exosomes exhibit less toxicity and immunogenicity which decreases the risk of adverse events associated with cancer therapy [109]. The role of cell-derived exosomes in GBM immunology and immunotherapy is being intensively studied [109].

Currently, the role of IL-17 and Th17 cells in exosome-based theranostics including diagnosis and treatment remains unknown. However, their applicability has been investigated in other malignancies. In gastric cancer, cancer cells can promote differentiation of Th17 cells through the release of exosome mi-R451 [110]. Overexpression of miR-451 exosome in tumor-infiltrating T cells was associated with more abundant Th17 distribution. In addition, patients with high miR-451 exosome expression in tumor-infiltrating T cells had a significantly worse prognosis. These results suggest that cancer-derived miR-451 exosome may be an unfavorable prognostic biomarker in patients with gastric cancer [110]. The Th17 differentiation-promoting activity of cancer-derived exosomes was also reported in colorectal cancer [111]. Colon cancer-derived exosomal miR-223-3p promoted M2 macrophage polarization resulting in increased secretion of pro-oncogenic IL-17 which intensified the proliferation and migration of colon cancer cells [112]. Breast cancer-derived exosomes through increasing the secretion of proinflammatory cytokines such as IL-17 may enhance the anti-tumor immunity and improve the efficacy of immunotherapy in breast cancer patients [113].

In conclusion, exosome-based theranostics including diagnosis, prognosis, and treatment of glioblastoma is a promising approach that may bypass common obstacles and limitations associated with standard techniques. To date, the association between IL-17 cytokine and exosomes in the context of glioblastoma remains mostly unknown. However, promising results of IL-17 and cell-derived exosomes in other malignancies support the need for further investigations of this issue in glioblastoma.

Conclusions

The role of IL-17 in GBM tumorigenesis is complex and multidimensional. IL-17 stimulates the PI3K pathway, thereby facilitating GBM cell survival, proliferation and migration. The promotion of GSC survival and self-renewal suggests that IL-17 may be associated with GBM recurrence and radio- and chemoresistance. IL-17 upregulated the expression of the BZW1 oncogene. IL-17 appears to be one of the main drivers of early-stage GBM growth via attenuation of anti-tumor immunity, promotion of survival under hypoxic conditions, and activation of GBM-promoting microglia.

The complex and highly immunosuppressive TME of GBM attenuates the host anti-tumor response. IL-17 facilitates the transmigration of Th17 into the CNS. Th17 can also be generated within the TME. Specific crosstalk between cells in the glioblastoma TME promotes tumor growth, infiltration, and escape from immune surveillance. Given the extensive cytokine network in the GBM niche, targeting a single cell population such as Th17 may not be sufficient to inhibit the tumor-promoting activity of IL-17. IL-17 drives GBM angiogenesis by mediating chronic inflammation and upregulation of VEGF, CD31, and HIF-1α. In addition, high expression of Th17 and VEGF is associated with poorer clinical outcomes in patients with GBM.

The role of IL-17 as a diagnostic and prognostic marker in GBM is ambiguous. The serum concentration of IL-17 may be associated with prognosis in GBM patients undergoing radiotherapy. Moreover, IL-17 levels may predict the clinical course of the disease. Evaluation of IL-17 level may also be useful as a recurrence marker. However, the potential use of IL-17 in clinical practice is associated with several limitations, including its lack of specificity and multifactorial pathogenesis.

Due to its aggressive clinical course and resistance to therapy, GBM is associated with a poor prognosis. There is an urgent need to introduce novel treatment strategies. Considering that IL-17 plays an important role in the pathogenesis of GBM, this cytokine is emerging as a novel therapeutic target in GBM patients. The results of preclinical studies investigating various molecules with anti-IL-17 activity are promising, but require further studies to evaluate their safety and efficacy in humans. Exosome-based immunotherapy and exosome-based theranostics including liquid biopsy are promising novel tools that may overcome common obstacles associated with glioblastoma management. Preclinical studies suggest that vaccine-induced Th17 cells and IL-17 may also have anti-tumor activity in GBM. By generating Th17 immunity, they provide a long-lasting anti-tumor immune response that, if associated with improved prognosis, may soon change the treatment paradigm.

In conclusion, due to its role in tumorigenesis, angiogenesis, and immune surveillance evasion, as well as its potential for aiding in the diagnosis and prognosis of GBM, targeting IL-17 or its signaling pathway shows promise as a novel therapeutic approach for treating GBM. Future research should focus on evaluating the efficacy and safety of anti-cancer molecules with anti-IL-17 activity.