In general, errors in a cell’s genome are the cause of the development and formation of neoplastic cells. The tumor’s microenvironment contains a number of factors that promote and sustain its growth. In addition, the resistance to applied therapies is also a result of tumor heterogeneity and its constant alterations [
154,
155]. Nonetheless, cancer has developed a number of immune surveillance evasion mechanisms. These include the avoidance of recognition by the down-regulation of MHC, impaired DC function, immunosuppressive TAMs, Natural Killer (NK) cell inhibition, T-cell anergy, immunosuppressive T-Cell recruitment using chemokines, regulatory T-cells (Tregs), T-cell apoptosis and extracellullar matrix. Several of these mechanisms are conducive to progression, the creation of their own environment for cell development, and cell death in their own favorable environment [
156‐
158]. Similar to other types of cancer, gliomas weaken the immune system through various pathways. Immunosuppressive ability of glioma plays a vital role for glioma survival. IL-10, IL-6, TGF, and PGE-2 were found to be immunosuppressive factors in the glioma microenvironment. In addition, the presence of GARP, a surface molecule, allows glioma to survive for a longer time by activating Treg cells [
53,
112]. On top of that, glioma induced tumor progression by weakening BBB integrity. This will lead to accelerate vasculogenesis and impaired arteries which result in hypoxia and promote tumor development [
153,
159]. Glioma also disrupted EC as a result of VEGF [
43,
44]. All of these pathways are frequently interconnected, resulting in a vicious cycle that promotes glioma survival and progression. Understanding what occurs within the microenvironment of glioma and which mechanisms are responsible for glioma development and progression will reveal how glioma could protect itself from the immune system.
The concept of immunotherapy for GBM
Decreased MHC expression in GBM frequently correlates with worse prognosis. MHC-I downregulation has previously been attributed to epigenetic and transcriptional dysregulations involved in the stabilization of NFkB, interferon regulatory factors (IRFs), and NOD-like receptor family CARD domain containing protein 5 (NLRC5). These dysregulations are possibly reversible, implying the possibility of reversing MHC-I downregulation in cancer. In addition, STAT3 inhibition, STING activation, chemotherapy, and radiation can all stimulate MHC-I expression [
160]. However, there are few trials targeting MHC-I in gliomas.
As previously stated, impaired DC proliferation will further impair CTL function [
45]. DC vaccines (DCVs) are a type of immunotherapy that aims to enhance DC activities. DCVs comprised of immunostimulatory APCs created in vitro utilizing CD14 monocytes cultured with GM-CSF and IL-4. In short, DCVs are basically DCs loaded with tumor antigen and injected into the patient [
161]. Autologous tumor lysate, cultured tumor cells from surgical specimens, irradiated autologous tumor cells, tumor RNA, or tumor related peptides were utilized as antigens. In a phase II GBM vaccine experiment, Wheeler and colleagues reported that 53% of GBM patients demonstrated a 1.5-fold increase in cytokine response following vaccination. Responders to vaccination have a longer median survival than non-responders (642 days and 430 days) [
162]. A large phase III clinical trials is needed to confirm DCV’s efficacy and safety in glioma, as results negating its benefits have also been published [
162].
In gliomas, TAM infiltration is dominated by tumor-supportive M2 macrophages. Because TAMs require colony-stimulating factor (CSF) for differentiation and survival, BLZ945, a CSF-1 inhibitor, was utilized to target TAMs in mice GBM models. Inhibition of CSF-1 can decrease the quantity of M2 macrophages, resulting in tumor regression [
163]. PLX3397 is a CSF-1 inhibitor that has the ability to cross the BBB and reduce TAMs, thus result in alleviation of tumor invasiveness in mice models of GBM [
163]. TAMs-targeted immunotherapy may be useful in the treatment of GBM. However, at the moment this therapeutic modality is still limited to in vivo models [
162].
NK cells have significant anti-tumor effects, particularly when CTL function is reduced. Although the number of NK cells in GBMs is deemed low, they retained cytotoxic activity [
80]. Enhancing NK cells’ oncolytic capacity might be achieved by counteracting their inhibition, that is through cutting the binding between MHC molecules and killer immunoglobin receptors (KIRs) [
95]. Ishikawa and colleagues demonstrated tumor volume decrease using autologous NK cells. In addition, they suggested that this response could be enhanced by combining autologous NK cells with an IL-2 dosage or radiation therapy [
164]. Another option is to use allogenic NK cells, which originate from an unrelated donor and are equipped with a KIR receptor that is incapable of recognizing MHC class I molecules. In allogenic NK cells, the KIR receptor does not recognize tumor MHC molecules, resulting in the absence of NK cells inhibition [
95].
Anti-CTLA-4 and Anti-PD-1 therapies have primarily been studied in T cells for their direct immunological implications (Fig.
2). Due to their roles as immune checkpoint, therapies targeting CTLA-4 and PD-1 are hypothesized to be able to “free” T cells from inhibition to fight tumor cells. CTLA-4 (CD152) is an inhibitory receptor which downregulates T cell function [
165,
166]. This receptor is mainly expressed on Tregs but might be upregulated on other subsets of T cells in pathologic condition, such as cancer. CTLA-4 suppresses the immune system indirectly by inhibiting signals via the co-stimulatory receptor CD28. CTLA-4 reduces immunological responses to weak antigens such as self- and tumor antigens by increasing the activation threshold of T cells [
167]. PD-1 binding to PD-L1 is involved predominantly in inhibitory immune signaling. Although the majority of circulating T cells lack PD-1, its expression can be stimulated by exposure to cytokines, such as IL-2, IL-7, IL-15, IL-21, and TGF-β [
167].
Neoantigens, which are formed from tumor-specific protein-coding mutations, are immune stimulatory and can operate as bona fide antigens that aid in tumor rejection. T-cell activation and subsequent tumor lysis driven by neoantigen vaccines offers an appealing precision medicine strategy. The process of developing a personalized neoantigen vaccination begins with a comparison of genetic data received from the patient’s peripheral blood mononuclear cells (PBMCs) and excised tumor tissue [
168]. Following administration of customized vaccinations, APCs come into contact with the neoantigens contained in the vaccine, thereby initiating the process of neoantigen MHC presentation [
169]. Immune responses mediated by T cells are triggered when a certain T cell receptor recognizes a particular neoantigen. In addition, these neoantigen-specific T lymphocytes expand, move toward the tumor site, and subsequently enter the tumor. Immune responses can be found that are CD4 positive (which enhances the immune response) or CD8 positive (which has a cytotoxic effect). Tumor cells that have been eliminated create an adaptive immunological memory response by releasing neoantigens [
170].
Adoptive T cell therapy, which entails the selection and development of antigen-specific T cell clones ex vivo, enables the enhancement of antigen-specific immunity without the in vivo restrictions associated with vaccine-based techniques. While some clinical responses have been found in vaccine trials, the amplitude of the induced T cell response has often been small or undetectable and has had a poor correlation with clinical responses. In comparison with vaccination methods, adoptive treatment procedures are capable of circumventing the in vivo restrictions that limit the amplitude and avidity of the targeted response. T cells with a given specificity, function, and affinity for a tumor can be selected in vitro and then expanded to achieve in vivo peripheral blood frequencies that are higher than those achieved by current immunization regimens and are consistent with the levels predicted to be required to mediate tumor elimination in murine tumor therapy models [
171]. In DCs, due to their capability to acquire, process, and present antigens to T cells, they are a critical component of immunization. While immature DCs in peripheral tissues acquire antigens readily, antigen presentation typically results in immunological tolerance due to a lack of costimulatory molecules [
172]. Immune tolerance is induced via a variety of methods, including T cell deletion and Treg cell growth [
173]. DCs laden with antigens that have been activated (mature) induce the differentiation of antigen-specific T cells into effector T cells with distinct roles and cytokine profiles. DC maturation is associated with a variety of cellular changes, including (1) decreased antigen-capture activity, (2) increased expression of surface MHC class II molecules and costimulatory molecules, (3) acquisition of chemokine receptors such as CCR7 that direct their migration, and (4) the ability to secrete various cytokines that regulate T cell differentiation including IL-12 [
174].
Current state of immunotherapy for glioma
DCVax-L
® has shown a benign safety profile in Phase 3 study, as it has consistently done in prior early stage trials, and in a large group of patients. Study by Liau and colleagues, showed that only 7 of the 331 Intention-to-treat (ITT) patients experienced any grade 3 or 4 adverse events that were at least possibly related to the treatment. With such a safety profile, DCV looks promising and can potentially be combined with a range of other treatments, including immune checkpoint inhibitors and targeted therapies [
175].
A review from Kennedy and colleagues shows that TAMs in glioma are a formidable foe, espousing an altered activation state within the local tumor microenvironment characterized by deficiencies in antitumor effector functions, upregulation of potent immunosuppressive mediators, and participation in tumorigenic loops of paracrine signaling [
176]. Given the compelling evidence that TAMs contribute significantly to the creation and maintenance of immunosuppression and tumor progression, it is unlikely that clinically effective immunotherapy against malignant gliomas will be achieved until we gain a better understanding of how to influence TAM function in the local tumor microenvironment [
176].
Golan and colleagues conclude that immunotherapy with NK cells seems to be a promising strategy for treating GBM patients. Furthermore, the use of techniques that increase direct cell-to-cell contact between GBM cells and NK cells could potentiate the antitumor effect [
177].
Liu and colleagues concluded that there is an association between CTLA-4 expression with clinicopathological findings and IDH mutation status in gliomas. Moreover, CTLA-4 was positively correlated with other immune-related proteins in glioma. Additional studies are needed to further explore the molecular mechanisms mediating CTLA-4 expression in gliomas and responses to anti-CTLA-4 therapy [
178].
CAR T-cell therapy has become a revolutionary approach for treating hematological malignancies and it has great potential for brain tumors. Land and colleagues discussed the various targets of CAR T-cell therapy, among which is the EGFRvIII [
179]. The EGFRvIII is the most common EGFR mutation that occurs in about 45% of GBM patients [
179]. In vivo study showed that CAR T-Cell targeting EGFRvIII improved survival of the subject animal, as well as reduced the tumor volume. The subject was mice implanted with EGFRvIII-positive glioblastoma cell line [
180].