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Abstract

Glioblastoma is an aggressive primary brain tumor that poses many therapeutic difficulties because of the high rate of proliferation, genetic variability, and its immunosuppressive microenvironment. The theory of cancer immunoediting, which includes the phases of elimination, equilibrium, and escape, offers a paradigm for comprehending interactions between the immune system and glioblastoma. Immunoediting indicates the process by which immune cells initially suppress tumor development, but thereafter select for immune-resistant versions leading to tumor escape and progression. The tumor microenvironment (TME) in glioblastoma is particularly immunosuppressive, with regulatory T cells and myeloid-derived suppressor cells being involved in immune escape. To achieve an efficient immunotherapy for glioblastoma, it is crucial to understand these mechanisms within the TME. Existing immunotherapeutic modalities such as chimeric antigen receptor T cells and immune checkpoint inhibitors have been met with some level of resistance because of the heterogeneous nature of the immune response to glioblastoma. Solving these issues is critical to develop novel strategies capable of modulating the TME and re-establishing normal immune monitoring. Further studies should be conducted to identify the molecular and cellular events that underlie the immunosuppressive tumor microenvironment in glioblastoma. Comprehending and modifying the stages of immunoediting in glioblastoma could facilitate the development of more potent and long-lasting therapies.

Keywords

glioblastoma immunoediting immunotherapy tumor microenvironment chimeric antigen receptor-T

Introduction

Glioblastoma, also known as grade IV astrocytoma, is the most common rapid growing malignant brain tumor developed from de novo (primary glioblastoma) or through progression from a lower grade (grade I/II) as well as from anaplastic astrocytoma (a grade III brain tumor developed from star-shaped brain cells called astrocytes).¹ Studies have shown that roughly 49% of initial malignant brain tumors are glioblastomas, with a small predominance in men and an increase in prevalence with age.² Patients with the condition have a dismal prognosis, with a median survival time of about 12-14 months. Less than 10% of patients survive two years after diagnosis, and only 5% make it to five years.³ Eventually, the majority of patients die as a result of the disease progression.

Both primary and secondary glioblastoma has shown poor response to checkpoint inhibitors and vaccinations in early clinical trials.⁴ High tumor heterogeneity, systemic immunosuppression, and local immune dysfunction have all been implicated as contributors to the failure of treatment for glioblastoma.⁵ The development of immunotherapy, a method that attacks the ways in which cancer cells and other solid tumors hide from the body’s defenses, is a significant step in this direction. Nonetheless, immunotherapy has failed to improve the prognosis of patients with glioblastoma.⁶ As a consequence, glioblastoma remains mostly intractable.

Understanding the complex interaction between glioblastoma and its immune system in the TME is crucial for developing effective and efficient treatments for glioblastoma.⁷ Cancer cells, normal brain cells, and immune system cells all coexist in the glioblastoma tumor microenvironment.⁸ These diverse cells communicate with one another by direct cell-cell contact or through soluble molecules such as cytokines and chemokines, and they affect tumor development through autocrine and paracrine signaling.⁹ The Glioblastoma immune microenvironment has been recognized as extremely immunosuppressive, offering a significant barrier to initiating immune-mediated killing of cancer cells where immune cells of the brain promote proliferation of cancer rather than destroying it.¹⁰ On top of that, glioma cells regulate tumor microenvironment functions through complex signaling networks, affecting biomass synthesis, cellular maintenance, and resistance to therapies for survival.¹¹ Here, cytokines, chemokines, matrix remodeling enzymes and growth factors are all examples of soluble molecules that play a role in mediating communication between tumor and surrounding cells.⁸ Therefore, development of effective new therapeutics requires an understanding of the processes behind tumor-mediated immune suppression in glioblastoma. Reversing this process may be crucial for the establishment of a successful immunotherapy for glioblastoma.¹² Immunoediting has recently come to prominence as an approach explaining how the immune system interacts with the selection of genetic mutations in cancer, along with how the immune system selects proliferating cancer cells as they are more capable of evading immune surveillance.¹³

Elimination, equilibrium, and escape are the three stages of cancer immunoediting in which the host immune system determines the course of development of tumors.¹⁴ Elimination destroys transformed cells, while equilibrium allows their survival. As tumors that have been immunologically molded expand, manifest clinically, and create an immunosuppressive microenvironment, the tumor is able to escape from the immune system.¹⁵ In terms of eliminating glioblastoma cells, the fundamental aims of cancer immunoediting are to limit and reverse development through these three stages, thus enhancing the immune system’s capacity of controlling tumor growth.¹⁴ On top of that, in the elimination stage, the innate and adaptive immune systems work together to detect a developing tumor and eliminate it before any outward symptoms appear. This may be thought of as an updated version of cancer immunosurveillance.¹⁶ Furthermore, in most cases, the immune system recognizes and destroys cancer cells; however, the cancer immunoediting idea foresees that if elimination is unsuccessful, tumor cells may enter an equilibrium phase during which they progressively develop and refine techniques to escape immune recognition and elimination.¹⁷

Although the entire immunoediting process is dependent on both innate and adaptive immunity, Research shows that even without adaptive immunity, innate immune cells are capable of participating in cancer immunoediting action, leading to the evolution of effector cells like natural killer (NK) cells and interferons (IFN) that produce M1 macrophages.¹⁸ IFN sensitivity is crucial at each of the three stages of cancer immunoediting.¹⁹

Even though immunoediting is capable of eliminating tumor cells with altered antigenic epitope profiles, many immune resistant varieties bypass the host immune system via multiple immunosuppressive molecular and cellular pathways.²⁰ Conflicting interactions between the immune system and tumor cells during these stages of cancer immunoediting leads to the development of a complex immunological microenvironment, which causes the acquisition of various levels of immunotherapy resistance in tumor cells.²¹ As cancer immunoediting highlights how the tumor microenvironment may promote tumor cell escape from immune surveillance and tumor immunity, the main challenge lies in understanding and controlling the complex interplay among the various components inside the tumor microenvironment.⁷

Immunoediting in Glioma

Phases of Immunoediting

Cancer immunoediting refers to the coevolutionary interplay between the immune system and the tumor cells.¹⁶ Also one of the main keys to this process is IFN signaling.¹⁹ The process of cancer immunoediting occurs when the tumors progress naturally, but the data from studies of individuals who have had cancer immunotherapies suggest that the process is reactivated as a result of treatment either wholly or partially.¹⁶ The three main stages of cancer immunoediting are elimination, equilibrium and escape (Figure 1).¹⁵

Figure 1.

Different phases of immunoediting.

The initiation of cancer turns non-malignant cells into cancer cells and facilitates the subsequent phases of immunoediting. In the elimination phase, both the innate and adaptive systems assist in recognizing the transformed cells which escape intrinsic tumor suppression while eliminating them prior to their clinically detectable state. Tumors that survive may enter the elimination stage, where net growth is restrained by the adaptive immune system. The equilibrium phase involves dynamic interactions between tumor and immune cells, with immune pressure causing genomic changes in tumor cells. Eventually, tumors may enter the escape phase, characterized by uncontrolled growth due to the activation of immunosuppressive or immune-evasive pathways.²²

The Elimination Phase

The elimination phase relates to cancer immunosurveillance in which diverse immune response elements identify and eliminate tumors.²³ However, the antitumor immune response in the brain is one of the most crucial mechanisms of the elimination phase in immunoediting. Two major concepts are involved in the elimination phase called the blood-brain barrier and immunological privilege.²⁴ The phrase “immune privilege,” is originated from skin grafting by the research of Peter Medawar on the central nervous system. It represents the belief that the central nervous system is immune-free compared to other parts of human body.²⁵ The generation of the blood-brain barrier is considered to be a mechanism consisting of a structural obstacle to the passive transport of molecules between systemic circulation and the brain generated by closely apposed capillary tight junctions.²⁶ Moreover, a growing body of research clarifies that the cells and chemicals could support antiglioma immune reaction; thus providing the foundation for the elimination stage of glioma immunoediting.²⁷

An outstanding success in the quest for specificity in cancer immunology was the molecular discovery of the first human tumor antigens.²⁸ Most antigens studied so far are presented by major histocompatibility complex (MHC) class I molecules and they are recognised by CD8⁺ T lymphocytes. Scholars believe that the identification of such antigens could be a fundamental step in the glioma immunoediting process that leads to its elimination.²⁴ Despite the fact that glioblastoma antigen cloning lags behind that of other cancer types,²⁹ proteins important in detection by adaptive and innate immune responses have been discovered. Proteins playing a role in detection by cellular and humoral adaptive and innate immunity (Table 1) are outlined.

Table 1.

Cellular and Humoral Glioma Antigens.

Antigen	Antigen type	Human leukocyte antigens allele	Expression in glioma	References
EphB6	MHC Class I	HLA-A24	Expression in glioma cell lines by RT-PCR	³⁰
EphA2	MHC Class I	HLA-A2	Variable in 19/19 astrocytomas and gliomas by IHC8	³¹
TRP-2	MHC Class I	HLA-A2	Variable expression in 30/47 GBM samples by IHC	³²
GLEA2	SEREX	NA	Detected in every glioma sample by Northern blot and RT-PCR analysis	³³
MICA/B	Innate	NA	IHC demonstrates a higher level of expression in glioma with some variation by tumor grade	³⁴

The blood-brain barrier (BBB) and restricted immune cell infiltration, together with the immunological privilege of the brain, make it difficult for CD8⁺ T cells to recognise tumors and antigens in the brain. However, via a variety of pathways, CD8⁺ T cells may still contribute to the identification and perhaps even the eradication of brain tumors, including gliomas.³⁵ The BBB limits, but does not entirely prevent, immune cells from entering the brain. Other immune cells, including CD8⁺ T cells, can partially enter the brain. They support immune surveillance by continuously scanning the surrounding environment of the brain for aberrant or pathogenic cells, including tumor cells.³⁶ Antigen-presenting cells (APCs) must deliver tumor antigens to CD8⁺ T lymphocytes in order for them to recognise and destroy tumor cells. Microglia and dendritic cells function as APCs in the brain and may expose CD8⁺ T lymphocytes to tumor antigens. APCs located at CNS boundaries is hypothesized to facilitate T cell entrance into the parenchyma during neuroinflammation.³⁷ The MHC class I antigen is presented to CD8 T lymphocytes by a CNS-resident APC, but its identification is unclear. Local antigen presentation plays a critical role in CD8 T cell infiltration of the widely infected the central nervous system. During Theiler’s murine encephalomyelitis virus (TMEV) infection, activated CNS-myeloid cells increase MHC class I expression and concentrate close to the hippocampal vasculature, which is a good area to engage with CD8 T cells trying to cross the BBB.³⁷

It is worth mentioning that no research has been conducted to provide proof that gliomas are in the elimination phase, so there is no confirmation that they disappear before they reach the clinical stage. Unlike other malignancies such non-Hodgkin lymphoma or Kaposi’s sarcoma, gliomas do not often develop from immunosuppressed conditions³⁸ despite some findings that indicate a greater frequency of gliomas in immunosuppressed patients. Directly demonstrating the elimination stage in patients is especially challenging proof of immune cells invading the tumors during the preclinical stages of gliomas, followed by the tumors’ spontaneous removal is needed. Transgenic mouse gliomas have recently emerged as a cutting-edge method that emulates the development of a variety of the genetic modifications observed in human gliomas, and has been used to demonstrate this. They also present a chance to examine whether immune cells infiltrate gliomas as they are forming, which is necessary for the elimination phase to exist. A transgenic mouse glioma model of spontaneous cancer was used in a study to examine early immune responses at early phases of glioma development.³⁹ The glial fibrillary acidic protein (GFAP) promoter was employed to precisely express the V¹²HA-ras in astrocytes in order to cause the growth of astrocytomas. At 12 weeks, tumors in asymptomatic mice exhibited CD4⁺ and CD8⁺ T-cell infiltration, indicating that the immune system may detect a growing glioma at an early stage. However, no information on the tumors’ ability to spontaneously disappear was provided.³⁹

The Equilibrium Phase

Due to the robust eradication of tumor cells in the previous phase, the tumor cells with decreased antigenicity will not overgrow in the equilibrium phase of immunoediting.¹⁵ Moreover, the equilibrium stage is characterized by a state of equilibrium between the tumor as well as the immune system, during which tumor cells and immune cells mutually shape one another.²³ While there is a static net influence on tumor growth, it is probable that the relationship is dynamic.²⁴ Immune pressure on tumor cells may cause them to develop genomic changes, which is a window of opportunity for immunoediting.⁴⁰ When more copies of this mutated gene are added together, the immune system becomes compromised and enters the immunological escape phase.

Last but not least, the immune system is of great importance in the selection of tumor variations that go on to develop unchecked and escape immunological control.⁴¹ It seems that the equilibrium phase in humans is best shown by the transmission of tumor cells from donors to recipients through organ transplants. Here, immunity is thought to limit the spread of occult neoplastic illness in the transplant donor, while immunosuppression allows the disease to progress in the transplant recipient. While extraneural dissemination of glial tumors is very uncommon, several investigations have shown that glioma may be passed on from liver and kidney donors to their recipients.⁴²

Although tumor cells have been observed to circulate in the circulation, gliomas often do not spread outside of the central nervous system.⁴³ According to the circumstances of these organ transplant cases, glioma cells in the donor individuals may have remained in a state of dormancy as a result of host immune stress, but after transplantation, these tumors grew in the donated organ that was transplanted into a host that had undergone pharmacological immunosuppression. A child with medulloblastoma who received a diagnosis at 17 months of age and who, 10 years later, required immunosuppressive medication in order to undergo a lung transplant due to the emergence of chemotherapy-induced pulmonary fibrosis is yet another instance of evidence that may point to the presence of an equilibrium stage in brain tumors. The histological analysis of liver metastases that were discovered 12 months after the transplant revealed an additional recurrence of the medulloblastoma.⁴⁴ According to mouse models, T-cells in particular may be in charge of limiting tumor development during the equilibrium stage.⁴¹ IFN, CD4⁺, and CD8⁺ T-cell reduction in mice given methyl-colantrene accelerated the growth of sarcomas as compared to NK cells. Furthermore, the reduction of CD4⁺ and/or CD8⁺ T-cells caused spontaneous lung metastases in a fibrosarcoma mice model, but these metastases do not occur in an immune-competent environment.⁴⁵ This indicates the significance of the connection between MHC-I molecules and T-cell receptors in maintaining tumor equilibrium. These metastases were extremely positive for MHC class I.

The Escape Phase

Downregulation of MHC expression or loss of the capacity to process and display antigens that are MHC compatible serves as a common mechanism by which many malignancies evade the immune system.⁴⁶ Furthermore, the presence or lack of the expression of the major histocompatibility complex could promote the immunoevasive nature in malignant glioma; hence, the significance of MHC class 1 expression in this type of cancer is ambiguous.²⁴ Due to their intrinsic heterogeneity, malignant glial tumors consist of cells that express varying quantities of MHC I and MHC II. Therefore, the glioma cell admixture may have varying degrees of MHC expression within a more general anatomic context where expression is exceptionally low.

Glioma uses a wide range of immunoevasive strategies affecting the MHC Class 1 pathway. A study has shown that more than 50% of the glioblastoma specimen did not have HLA Class 1 antigens⁴⁷ and another study showed that glioblastoma tissue had a major downregulation of β2 microglobulin which happens to be a major component of MHC heterodimer complex. Apart from that, it was concluded in another study that glioblastoma cells could lose the antigens that were presented once the immune response is initiated.⁴⁸ The complexity of the roles of MHC in glioma immunobiology has been shown by recent research.²⁴ Some of the potential mechanisms of glioma immunoediting evasion (Table 2) have been documented.

Table 2.

Potential Mechanism of Glioma Immunoediting Evasion.

Tumor Cells Intrinsic Alteration
Evasion of Adaptive T-cell	Antigen loss.⁴⁸
	Decreased TAP1, LMP2.⁴⁹
	Upregulated B7-H1.⁵⁰
	Dampening B7 expression.⁵¹
Innate NK Cell Activity Disruption	Increased HLA-G.⁵²
	Release of soluble NKG2D ligands.⁵³
	Increased MHC Class 1 expression.⁵⁴
Surrounding Immune Cells Extrinsic Alteration
Increased Treg Activity	Increased proportion at tumor bed.⁵⁵
	Increased proportion in systemic/blood immune effects.⁵⁶
Disrupted Cytokine Milieu	TH2 skew among TILs.⁵⁷
	TH2 skew among blood lymphocytes.⁵⁶
Mixed Intrinsic and Extrinsic Actions
STAT3 Activation	Enhanced STAT3 activation.⁵⁸
	Increased immune tolerance.⁵⁹
	Decreased innate and adaptive immune activation.⁶⁰

Cytokine Dysregulation

It is important to maintain the orchestration of immune systems facilitated by intercellular communication via cytokines and chemokines between the immune cells.⁶¹ Direct effector actions and the production of genes required for altered cell function may be triggered by the binding of a cytokine or chemokine to its associated receptor on the cell surface (Table 3).⁶¹

Table 3.

Key Cytokines, Chemokines and Their Receptor in Glioblastoma.⁶¹

Ligand	Alternative name	Receptor
Colony-stimulating factor 1 (CSF-1)	M-CSF	CSF-1R
Interleukin-6 (IL-6)	HGF/BSF-2/HSF	IL-6 receptor
Monocyte Chemoattractant Protein 1 (CCL2)	MCP-1	CCR2, CCR4
Stromal cell-derived factor 1 (CXCL12)	SD-1/PBGF	ACKR3, CXCR4
C-C motif chemokine ligand 5 (CCL5)	RANTES	CD44, CCR1, CCR5

It has been shown via extensive research that individuals with glioma have an abnormal immune response because of the improper or dysregulated release of a variety of cytokines and they are responsible for the immunosuppressive effects.²⁴ A wide range of immune-dampening molecules is secreted by the tumor cells such as Prostaglandin E2, Interleukin 10 (IL-10) and Transforming growth factor-β (TGF-β) isoforms. It is worth mentioning that the isolation of human TGF-β1 and TGF-β2 was done from the glioblastoma supernatants.⁶² However, these cytokines can have several inhibitory functions including the downregulation of MHC Class II expression and presentation, the suppression of macrophage antigen presentation, suppression of Th1 cytokine synthesis, suppression of the proinflammatory cytokine production as well as the inhibition of NK cell-mediated cytotoxicity.⁶³

Glioblastoma cells have high levels of expression of the CXCR4 receptor, which is bound by the chemokine CXCL12. Tumor cell movement, survival, and multiplication are all aided by this interaction. Additionally, CXCL12/CXCR4 signaling promotes angiogenesis and tumor progression by making it easier to recruit endothelial progenitor cells.⁶⁴ Conversely, T lymphocytes, macrophages, and monocytes are drawn to the TME by CCL2. Tumor-associated macrophages (TAMs), which have the ability to inhibit the immune system and accelerate the growth of tumors, are drawn to glioblastomas in response to CCL2.⁶⁵ Basophils, eosinophils, and T lymphocytes are all recruited by CCL5. It has been demonstrated that CCL5 increases the invasion and proliferation of tumor cells in glioblastoma. Additionally, it helps inhibit the immune system by attracting regulatory T cells (Tregs) to the TME.⁶⁶

Studies have proven that lymphocytes alongside glioma cells allow steering the antiglioma immune responses towards Th-2 type cytokine production in glioma patients.²⁴ An increased level of IL-10 is secreted by the peripheral blood lymphocytes of the patients while they have been failed to elaborate Interleukin 12 (IL-12).⁶⁷ Such cytokine dysregulation can also be seen in the Tumor-infiltrating lymphocytes which have been isolated from the glioma samples and further studies unveiled some interesting insights that showed the expression of predominant Interleukin 4 (IL-4), granulocyte macrophage colony stimulating factors (GM-CSF). Nevertheless, majority had not exhibited the increased expression of TNF-β, Interleukin 2 (IL-2) and Interferon gamma (INF-Ɣ) as compared to normal peripheral blood cells.⁵⁷ Therefore, it seems that glioma patients suffer from substantial dysregulation in the coordination of a robust antitumor immune reaction, which eventually results in a switch from the secretion of the crucial Th1-type cytokines to that of conventionally immunosuppressing molecules.

IL-6 sustains the progression of tumor as they act directly on the glioblastoma cells by inducing anti-apoptotic pathways while promoting invasion.⁶¹ However, IL-6 has the ability to act as a prognostic factor among the patients suffering from glioblastoma as high IL-6 gene expression seemed to be associated with poor patient survival as per the datasets derived from the Respiratory of Molecular Brain Neoplasia Data as well as the Cancer Genome Atlas.⁶⁸ On the other hand, IL-10 represses the immune system as they facilitate the downregulation of antigen presentation, blockage of the maturation of dendritic cells; and all these phenomena can majorly hinder the effector function of T cell.⁶⁹ Another important soluble protein responsible for immunological suppression is macrophage migration inhibitory factor (MIF). Expressions of MIF were shown to correlate with glioma grade and were considerably higher in gliomas than in the normal brain.⁷⁰

MHC molecule expression is downregulated in the immune-privileged brain environment by tumor cells, which makes these molecules less visible to cytotoxic T cells.⁷¹ Additionally, immunological checkpoint pathways like PD-1/PD-L1 are activated by glioblastomas, which prevents T cell activation and inhibits antitumor responses.⁷² These tumors often enlist Tregs along with myeloid-derived suppressor cells (MDSCs) to produce an immunosuppressive milieu. In order to avoid being recognised by the immune system, glioblastomas may also undergo antigenic modification, changing their antigen profile. Having stated that, cancer cells have the ability to create variations devoid of characteristics that make them accessible for T-cell detection and death.⁷³ This allows them to avoid immune system assault. Through mutations or gene deletions, cancer cells may avoid being recognised by T lymphocytes, which results in the downregulation of vital proteins involved in the antigen presentation apparatus. In addition, it was discovered that LMP2 protein remained unaffected whereas malignant gliomas had undetectable or extremely low amounts of TAP1 protein and were not expressing TAP1 mRNA.⁷⁴ Additionally, they discovered that IFN-g and IFN-β enhanced the production of TAP1 and MHC class I molecules, indicating that malignant glioma cells might have become less immunogenic owing to decreased TAP1 expression. It is also known that regulatory T cells inside the tumor microenvironment significantly contribute to the inhibition of regional anti-tumor immune responses in a variety of human malignancies.

In the context of glioblastoma, the concept of immunoediting and its phases is complex and not fully similar to that of tumors that are not in immune-privileged places.⁷⁵ The BBB and the restricted immune surveillance present in the brain give the brain an immune-privileged status that affects the immunoediting mechanism. Cancer cells are identified and eliminated by the immune system throughout the elimination phase. It may be more difficult for immune cells to penetrate and destroy tumor cells in gliomas due to the BBB’s presence and the distinct brain microenvironment.⁷⁶ Although they may have lethal effects on glioma cells as immune cells like microglia and invading T cells play a part in surveillance. A balance between tumor cell proliferation and immunological regulation defines the equilibrium phase. This phase may take longer in gliomas because of the immune-privileged environment. Immunological responses can be inhibited by immune checkpoints and regulatory mechanisms, such as the increase of PD-L1 expression on glioma cells.¹² During the escape phase, tumors create defences against immune detection and eradication. Immune checkpoint drugs may not be as effective against glioblastoma because of this resistance. The immunosuppressive tumor microenvironment and the occurrence of immunosuppressive cells like regulatory T cells are two possible causes of this resistance.⁷⁷

Immunoediting in Cancer Patients

Numerous lines of evidence now show how the immune system helps cancer patients through eliminating affected cells and promoting tumor escape. In cancer patients, such a foundation for the creation of several cancer immunotherapies has been established by the finding that cancer immunoediting also takes place.⁷⁸ The effectiveness of these immunotherapies in lowering T cell repression and enhancing tumor detection in human cancer patients supports the idea that the immune system plays a key role in suppressing or altering the course of clinically relevant malignancies.

One important piece of evidence suggesting the immune system has a role in the development of human cancer is the finding that many cancer patients display spontaneous immunological responses to their diseases.^16,79,80 Antibodies to antigens released by tumors or the existence of CD4⁺ or CD8⁺ T cells are indicators of these autonomic reactions. Although these responses are seen in tumors that are clinically recognizable, immune reactivity to the tumor is not directly linked to immune protection or tumor regression. The capacity to forecast a patient’s outcome by considering the presence and calibre of intratumoral immune response offers more proof that the immune system may control the growth of tumors. The concept was inspired by the discovery that patients with colorectal cancer (CRC) who had spread CD8⁺ T cell infiltrates across the tumor nest saw better clinical outcomes than those whose TILs were confined to the stroma or margins of their CRC tumours.⁸¹ Subsequent studies revealed that the proportion of CD8⁺ T cells to Tregs appeared important, since a larger ratio was associated with a better clinical result. Furthermore, increased suppressive cells such M2 polarized macrophages are associated with a poorer prognosis for patients.^82,83 Finally, the enhanced clinical results observed in patients receiving immunotherapies provide proof of the immune system’s involvement in tumor editing. After checkpoint blockade therapy, reviving CD8⁺ TILs suggests that the tumour site has an active, tumor-specific immune response. Reducing tumor-mediated suppression can also lead to tumour regression in a significant proportion of patients. Furthermore, responsiveness to anti-CTLA-4 treatment for melanoma^84,85 and anti-PD-1 therapy for non-small cell lung cancer⁸⁶ is correlated with the mutational load inside tumors. In a different trial, patients with colorectal malignancies who lacked proper mismatch repair function benefited more clinically from PD-1 blocking than did patients with colorectal cancers that had normal mismatch repair function.⁸⁷

Immunoediting during Immunotherapy

It is very important to understand the difference between immunotherapy and immunoediting. Immunoediting is a process through which a tumor-immune relationship gradually develops, whereas immunotherapy is a strategic action aimed at shifting the balance in favor of the immune system. Immunoediting occurs in three phases: elimination, equilibrium, and escape, which depict different phases of the immune-tumor relationship. On the other hand, immunotherapy can target a particular cancer phase to increase immune-mediated elimination, achieve immune control, or prevent immune evasion.⁸⁸ The fact that cancer immunoediting is an evolving procedure in human individuals undergoing cancer immunotherapy for well-established advanced tumors is not to be overlooked. If effective, cancer immunotherapy can boost the tumor’s eradication for long-term benefit by modifying or even restoring a compromised immune response in the tumor microenvironment. In the event that immunotherapy is unable to eradicate the tumor entirely, the patient may experience the equilibrium phase, in which they respond to treatment partially yet have long-lasting and consistent improvements.⁸⁹

Since clinically evident tumors have advanced to the cancer immunoediting escape phase, the therapy’s objective is to accelerate elimination or to preserve equilibrium. Cancer immunoediting presumably happens in response to immunotherapy as well as over the course of a tumor’s natural evolution.⁹⁰ This can lead to secondary or acquired resistance to immunotherapy, which is characterised by an initial clinical response (incomplete elimination or equilibrium) and its progression (secondary escape). For instance, cancer patients who get objective responses from Immune Checkpoint Therapy (ICT) commonly have long-lasting effects, although even with ongoing therapy, delayed relapses are seen often.⁹¹ Due to the large number of patients receiving ICT treatment, secondary resistance has been the subject of the most research in this area.⁹² The precise mechanisms underlying secondary resistance remain unclear, although those that have been identified may be broadly classified as influencing either the immune system’s ability to identify tumors or its ability to eliminate them.

Evidence of cancer immunoediting through intrinsic tumor alterations in antigen presentation has been found in a variety of tumor types; this might lead to immunotherapy resistance.⁹² The Rosenberg group produced some of the first clinical data showing the loss of β2M following immunotherapy. In melanoma patients who had initially exhibited a clinical response to many immunotherapy therapies, they discovered β2M mutations in the tumors that were on the rise, such as ACT, IFNα, and/or IL-2.⁹³ Other studies reported similar findings in case reports describing acquired loss of HLA-I/MHC-I expression in metastatic melanoma lesions that relapsed, including one patient with melanoma who relapsed after receiving numerous kinds of immunotherapy.⁹⁴ Acquired abnormalities in β2M, such as homozygous truncating and frameshift mutations and LOH, have been linked to secondary resistance to ICT.^95,96 Patients receiving a customised mRNA vaccine in a cancer vaccine context showed impressive vaccine-induced tumor-specific T cell responses as well as indications of decreased metastases following immunization.⁹⁷

Furthermore, acquired aberrations in IFN-γ signaling pathways have been shown to induce tumor escape in preclinical models and have been observed in patients at the development of secondary resistance.⁹⁸ When anti-PD-1/PD-L1 inhibition was used to preclinical orthotopic pancreatic ductal cancer animals, targets were seen. Tumor escape variants, on the other hand, were discovered to have abnormalities in TAP1 expression caused by IFN-γ, which is necessary for peptide delivery into the ER and eventual loading onto MHC-I.⁹⁹ It has been demonstrated that loss-of-function mutations and LOH in the human genes encoding JAK1 or JAK2 were acquired by two patients who responded to ICT but subsequently developed.¹⁰⁰ According to a separate research, immunotherapy can favourably select against putative neoantigenic mutations and encourage divergent clonal development within tumors, especially if treatment does not completely eliminate the tumour.¹⁰¹

It is important to understand that, despite compelling evidence that cancer immunoediting increases acquired resistance to immunotherapy, the exact mechanism by which this occurs is typically inferred from indirect data, if not expressly stated. Furthermore, the processes behind tumor editing probably vary based on the kind and location of the disease as well as the immunotherapy used. It is critical to further define cancer immunoediting across a spectrum of tumor types and immunotherapies in order to better anticipate and overcome acquired resistance.

Immunoediting as a Potential Immunotherapy

Immunotherapy and its Major Challenges

Immunotherapy is a type of immunological intervention that stimulates the immune system to identify and eliminate cancer cells. In fact, blocking inhibitory immune checkpoint molecules has been proven to be particularly successful with this therapy against a wide variety of cancers.¹⁰² One of the potentially transformative and viable approaches to cancer treatment is immunotherapy even though the therapeutic interventions tended to fail most often due to the plasticity of cells in the tumor microenvironment.¹⁵ However, the administration of cancer immunotherapies has been limited only to patients with advanced-stage cancers including patients with relapsed and recurrent disease after a bunch of treatments.²² Advanced-stage cancer patients report increased immune dysfunction and because of this reason, they also have an insufficient response to immune-checkpoint inhibitors.¹⁰³ The results of neoadjuvant immunotherapy administered before to surgical intervention are superior to those of surgery followed by adjuvant immunotherapy in a variety of malignancies, including mammary cancer in mice and melanoma in humans, according to preclinical studies and early clinical trial data.¹⁰⁴ Based on these findings, it is reasonable to hypothesize that improving the timing of immunotherapy in conjunction with cancer surgery as well as other standard-of-care therapies (such as chemotherapy, radiation, and targeted therapy) might further enhance antitumor responses among patients.²²

This growing interest in immune checkpoint inhibition in glioma has piqued the attention of academics in recent years, and their discoveries have sparked their interest. Combining anti-PD-1 as well as anti-CTLA-4 blocking Abs, however, has not been demonstrated to increase overall survival in previous investigations.¹⁰⁵ Yet with resectable glioblastoma (GBM), the neoadjuvant nivolumab showed no discernible improvement, and the median overall survival had been 7.3 months.¹⁰⁶ Moreover, Nivolumab (anti-PD-1 blocking Ab) was unable to demonstrate an advantage over bevacizumab (anti-VEGF blocking Ab) in a phase III study of patients with recurrent glioblastoma, and both treatments resulted in median overall survival rates that were statistically indistinguishable.¹⁰⁷ It is worth mentioning that most glioblastoma patients had their symptoms worsen within the first year of therapy with bevacizumab and diffuse infiltrative recurrence was seen in a subset of these individuals. Some preliminary in vitro evidence suggests that bevacizumab resistance arises from the activation of additional proangiogenic agents and invasion processes.¹⁰⁸ Bevacizumab affects these changes in expression patterns; hence it might be argued that this is an innovative use of immunoediting and therefore, in order to overcome resistance to antiangiogenic drugs, treatment techniques that target both angiogenesis and invasion are required.

The use of immunoediting treatments is heavily influenced by the pathology of glioblastoma, making the distinction between primary and recurrent cases necessary. Conventional therapies for primary glioblastoma include of surgery, radiotherapy, and chemotherapy with temozolomide; however, given the high recurrence rate and dismal overall prognosis of the disease, novel strategies are imperative. Immunoediting treatments have been investigated, such as checkpoint inhibitors (nivolumab and pembrolizumab), which target the PD-1/PD-L1 pathway to improve the immune response against tumor cells.¹⁰⁹ The adaptive resistance mechanisms of the tumor and the changed TME after initial therapies make recurrent glioblastoma harder to treat. In this regard, it has demonstrated potential to combine checkpoint inhibitors with alternative modalities like as CAR T-cell treatment, in which T cells are modified to produce chimeric antigen receptors directed against tumor-specific antigens including EGFRvIII and IL13 Rα2.¹¹⁰ Furthermore, the identification of patients who may benefit from these treatments can be guided by the use of neoantigens and tumour mutational burden (TMB) as biomarkers.¹¹¹ The necessity for individualised therapy regimens based on particular pathologies is highlighted by the fact that the effectiveness of these medicines in prolonging OS is still an open question.

Due to immunotherapy’s wide usage, new clinical concerns have arisen, such as when to use immunotherapy in cases of medical conditions that are still in the earlier stages, how to best optimise therapy’s dosage, timing, and duration, which biomarkers are most useful for selecting patients, and how to create new surrogate endpoints that accurately reflect the effect of immunotherapy on overall survival (OS) in the course of treatment.¹¹² One appealing treatment option for micrometastatic conditions is adjuvant immunotherapy. Regarding stage IIB-III melanoma, IFN-α is licenced for adjuvant therapy (high dosage IFN-α¹¹³ in the USA and Europe, low dose IFN-α¹¹⁴ in Europe for stage II melanoma, and pegylated IFN-α for stage III melanoma in the USA¹¹⁵ in the USA). Since better relapse-free survival (RFS) has not consistently translated into extended OS, adjuvant treatment with IFN-α has had a little effect, according to a meta-analysis of many randomized phase III studies.^116,117 Advantages of adjuvant IFN-α therapy are predicted by tumor ulceration.^118,119 Negative results in the vaccination arm caused the early termination of other adjuvant vaccine studies,^120,121 indicating that adverse outcomes are also possible. A growing body of research indicates that while checkpoint inhibitor dosages increase response rates, they do not extend OS. Lower dosages are recommended since greater doses also increase the incidence of irAEs. Phase II studies have investigated the utilisation of various ipilimumab dosages in great detail.¹²² In advanced melanoma, a randomised phase 3 study directly compared 3 and 10 mg/kg of ipilimumab.¹²³ With 10 mg/kg, the median OS at the 43-month follow-up was 15.7 months, but with 3 mg/kg, it was 11.5 months. The rate of drug-related toxicity was greater in patients receiving the high dosage of treatment.

Current Therapeutic Options

While platinum-based medicines have a >90% cure rate for testicular cancer,¹²⁴ this percentage is not seen with gliobastoma. The major barriers of tumor heterogeneity, CNS penetration, and drug resistance must also be surmounted by pharmacological treatments for glioblastoma. CAR-T therapy, a form of cellular immunotherapy, has shown promise, particularly in treating hematologic malignancies. In this approach, autologous or heterologous T cells are isolated from a donor’s peripheral blood, reprogrammed the T cell receptor (TCR) of therapeutic target by retroviral transduction and then infused the amplified engineered CAR-T to the patient.¹²⁵ The process of CAR-T engineering and application in the clinic is shown (Figure 2).

Figure 2.

Chimeric antigen receptor-T engineering to clinical application.

Peripheral blood mononuclear cells are (PBMC) collected from donors (healthy or patient) by leukapheresis. Engineering of CAR-T cells is performed after isolation of T cells from PBMC and reprogramming by retrovirus mediated gene transfer technique.¹²⁶ After current good manufacturing practice (cGMP) production of engineered CAR-T, these can be infused to treat patients along with lymphodepleting chemotherapy.

Although antibody and vaccination approaches have been used to target glioblastoma antigens with varying levels of success, CAR-T therapy may provide benefits over existing treatments.¹²⁷ In the GD2 CAR treatment, T cells are genetically altered to identify and target cancer cells expressing GD2, a protein frequently present on the surface of glioma cells.¹²⁸ In addition, targeting the epidermal growth factor receptor (EGFR) in certain gliomas has also gained interest in recent years. Detail information regarding clinical trials of CAR T-based treatment for glioblastoma has been provided (Table 4), outlining various targets and associated CAR designs, along with the current status and indication of the clinical trials.

Table 4.

CAR-T and ICI Clinical Trials for Glioblastoma: Successes and Failures.

CAR-T
Targets	Phases	CAR Design	Status	Indications	Identifier
IL3Rα2	I	IL13-CD3ζ CD8 + cytotoxic T-lymphocyte clones	Completed	Recurrent/refractory malignant glioma	NCT00730613
IL3Rα2	I	IL3Rα2-specifc CAR with 4-1BB co-stimulation	Ongoing	Leptomeningeal glioblastoma	NCT04661384
IL3Rα2	I	IL3Rα2-targeted CAR	Ongoing	Glioblastoma	NCT04003649
EGFRvIII	I, II	EGFrvIII-specifc CAR T expressing 4-1BB and TCRζ	Completed	Glioblastoma	NCT03726515
EGFRvIII	I	EGFRVIII-4-1BBζ CAR	Terminated	Glioblastoma	NCT02209376
EGFRvIII	I	EGFRvIII-targeted CAR	Terminated	Recurrent glioblastoma	NCT03283631
HER2	I	HER2-CD28ζ virus-specifc T cells	Completed	Glioblastoma	NCT01109095
HER2	I	HER2-specifc, hinge-optimized, 4-1BB-co-stimulatory chimeric receptor	Ongoing	Recurrent/refractory glioblastoma grade III/IV	NCT03389230
B7-H3	I,II	B7-H3-targeted CAR	Ongoing	Recurrent/refractory glioblastoma	NCT04077866
GD2	I	Anti-GD2 CAR	Completed	Recurrent/refractory glioblastoma	NCT02761915
GD2	I,II	Anti-GD2 CAR T cells	Ongoing	Recurrent/refractory glioblastoma	NCT03373097
GD2	I	GD2-specifc CAR	Ongoing	Intrinsic pontine glioma, spinal diffuse midline glioma	NCT04196413
EphA2	I,II	EphA2-specifc CAR	Withdrawn	Malignant glioma	NCT02575261
CLTX	I	CLTX (EQ)-CD28-CD3 zeta-CD19t-expressing CAR T lymphocytes	Ongoing	MMP2 + recurrent or progressive glioblastoma	NCT04214392

ICIs
Trial No	Phases	Duration	Target	Indication	Outcome	Reference
NCT02336165	II	2015	PD-L1	Durvalumab + RT (n = 40)	OS- 12 months: 60%	¹²⁹
NCT03047473	II	2017-2021	PD-L1	Avelumab (n 30)	Ongoing	¹³⁰
NCT03174197	II	2017-	PD-L1	Atezolizumab + TMZ (n = 50)	OS: 17.1 mo	¹³¹
NCT03291314 GLIAVAX	II	2017-	PD-L1	Avelumab + axitinib (n = 54)	PFS- 6 months: 18%	¹³²
ISRCTN84434175 Ipi-Glio	II	2018-	CTLA-4	Ipilimumab + TMZ (n 80)	Ongoing	¹³³
NCT02337686	II	2015-2020	PD-1	Pembrolizumab + Surgery (n = 15)	PFS-6: 53%	¹³⁴
NCT02337491	II	2015-2020	PD-1	Pembrolizumab + bevacizumab (n = 50)	PFS-6 months 26 vs 6.7%	¹³⁵
NCT02017717 CheckMate 143	III	2014-	PD-1	Nivolumab (n = 184)	OS-12 months: 42%	¹³⁶
NCT02617589 CheckMate 498	III	2016-2021	PD-1	Nivolumab + RT (n = 280)	Non-improved OS	¹³⁷
NCT02667587 CheckMate 548	III	2016-	PD-1	Nivolumab + RT + TMZ	Ongoing	BMS press Release

Clinical trials for Glioblastoma immunotherapy failed
Trial No	Phase & status	Target	Indication	Outcome	Reference
Check Mate 498	Phase III	anti-PD-1 (nivolumab)+RT vs TMZ + RT	Glioblastoma -No improvement of mOS with anti-PD-1+RT (13.4 months) vs control treatment (14.9 months)	Primary endpoint unmet	BMS press release; ClinicalTrials.gov
ACT IV	Phase III	Peptide vaccine targeting EGFRvIII (rindopepimu) + TMZ vs placebo + TMZ	Glioblastoma	Primary endpoint unmet - No improvement of mOS with rindopepimut (20.1 months) vs control group (20.0 months)	¹³⁸
Check Mate 548	Phase III	anti-PD-1 (nivolumab)+SOC vs placebo + SOC	Glioblastoma	Primary endpoint unmet	BMS press release
NCT 00045968	Phase III	Dendritic cell vaccine (DCVax®-L) + SOC vs placebo + SOC	Glioblastoma	Placed on hold for unknown reasons	¹³⁹
Check Mate 143	Phase III	anti-PD-1 (nivolumab) vs anti-VEGF (bevacizumab)	Glioblastoma	Primary endpoint unmet - No improvement of mOS with anti-PD-1 (9.8 months) vs anti-VEGF (10 months)	¹³⁶

Even though CAR-T showed great promise in treating cancers, challenges in treating glioblastoma with CAR-T include the heterogeneous nature of GBM TME and potential toxicities such as cytokine release syndrome (CRS) and neurotoxicity.¹⁴⁰ Immunosuppressive nature of GBM TME is solely regarded as the primary obstacle to effective CAR-T therapy. In addition, the off-target effect is another hinderance of CAR-T cell therapy to treat GBM, where CAR-T cells are unable to recognise GBM tumor specific antigens (TAAs) and randomly target the body’s own protein causing damage to normal tissue cells.¹⁴¹ Therefore, concerns about neurotoxicity persist in the administration of CAR-T cells to the brain, which may occur independently or in tandem with CRS. While the exact mechanism (s) underpinning CAR T cell-mediated neurotoxicity are yet unknown, it is believed that CNS endothelial cell activation is one example.¹⁴²

Several Phase II clinical studies focused on treating cancer were carried out between 2015 and 2021. The studies encompass a variety of ICIs approaches, including Nivolumab, Durvalumab, Avelumab, Atezolizumab, Ipilimumab, and Pembrolizumab, often in combination with radiation or surgery. These trials specifically target PD-L1 and PD-1, with reported results detailing survival rates, progression-free survival measures, or ongoing investigations. However, the outcome has not been as promising, as the primary objectives could not be achieved using the immunotherapy treatments (Table 4).

At present, the uses of nanomedicine for drug delivery to the brain presents a potential solution to overcome challenges in cancer immunotherapy.¹⁴³ Polymer coated nanoparticles (NPs) can bypass the BBB, facilitating the administration of immunomodulatory drugs to GBM TME. While NPs may not directly alter immunoediting, its role in improving drug delivery to the brain complements immunotherapies like ICIs, CAR-T cells, and cancer vaccines.¹⁴⁴

Drug delivery to the brain via nanomedicine has showed promise and may be helpful for a number of neurological and neurodegenerative diseases.¹⁴⁵ The use of nanomedicine for brain drug delivery may have a limited direct impact on changing immunoediting. In order to affect immunoediting, the immune system must interact with cancer cells, either blocking or boosting cancer cell proliferation. In order to increase the delivery of immunomodulatory or therapeutic drugs to tumor locations, nanomedicine plays a key role in cancer immunotherapy.¹⁴³ It may boost the immune system’s capacity to identify and destroy cancer cells. Bypassing the blood-brain barrier, a particular obstacle that can obstruct the transport of therapeutic drugs to the brain, can be helpful in the context of brain tumors. Drug administration to the CNS can be facilitated by using polymer coatings and NPs to circumvent the BBB.¹⁴⁶ Multiple advancements in the diagnosis and treatment of nervous system diseases, brain tumors, and trauma have been made as a result of this technology.¹⁴⁷ It is important to note that the lipophilic properties of lipid NPs allow them to enter the brain by a variety of transport channels, including receptor-mediated endocytosis, transcytosis, and the paracellular pathway.¹⁴⁸ Additionally, NPs can target particular cells by coating or conjugating ligands, and by using particular ligands, they can pass the blood-brain barrier by receptor-mediated transcytosis.

The alteration of immunoediting is more directly tied to immunotherapies and the manipulation of the immune response, including checkpoint inhibitors, CAR T cell therapy, and cancer vaccines; even if nanomedicine can aid in the delivery of medications to the brain. Recent developments in nanomedicine have nonetheless demonstrated tremendous promise in addressing the limitations of cancer immunotherapy. Nanoscale cancer vaccines that affect the STING pathway, nanomaterials that alter TME, and nano-agents that trigger an immune response with immune checkpoint inhibitor synergy have all been reported for use in cancer immunotherapy.¹⁴⁹ Immunotherapeutic drugs, such as immune checkpoint inhibitors, can be packaged and delivered to cancer locations using nanoparticles.¹⁴⁴ By increasing the local concentration of these substances in the tumor microenvironment, this tailored medication administration may change the immunoediting process.

Recent Advancements in NK Cell-based Immunotherapy

Because NK cells can identify and eliminate tumor cells without the necessity for antigen presentation, NK cell-based immunotherapy has become a viable therapeutic option for glioblastoma in recent years. Genetically NK cells, specifically CAR-NK cells, dual antigen-targeting CAR-NK cells, and adapter CAR-NK cells, are among the most advanced approaches that are demonstrating considerable potential in overcoming the immunosuppressive tumor microenvironment of glioblastoma and improving anti-tumor activity.¹⁵⁰

Glioma therapy has shown great promise for CAR-NK cells, which capitalise on the innate cytotoxicity of NK cells and the improved selectivity offered by the chimeric receptor. CAR-NK cells provide safety benefits because of their allogeneic compatibility and non-cytotoxic effects in clinical settings, in contrast to CAR-T cells, which depend on autologous sources and raise safety issues such cytokine release syndrome.¹⁵¹ The EGFR and its mutant version EGFRvIII, both of which are frequently seen in glioblastoma, are examples of particular antigens that these cells are made to recognise and bind to Research has shown that NK cells expressing EGFRvIII alone are less stable in the circulation than NK cells expressing C-X-C motif chemokine receptor 4 and an MR1 antibody, which together increase the chemotaxis to C-X-C motif chemokine 12, which is referred to as stromal cell-derived factor 1 produced by glioma cells.¹⁵² The capacity of CAR-NK cells to start eliminating of cancer cells without the need for CAR is one of its main advantages. This is because NK cells are naturally able to identify and eliminate cells depending on how differently their MHC molecules are expressed. Because they have two purposes, CAR-NK cells are a flexible choice for immunotherapy, especially when tumor heterogeneity might reduce the effectiveness of single-target treatments.

CAR NK cells that target two or more antigens at once are known to be able to overcome the difficulties presented by the heterogeneous nature of glioblastomas. Dual-antigen targeting can be applied to point CAR NK cells to a set of antigens that are up-regulated in cancer cells and down-regulated in normal cells leading to enhanced tumor specificity and NK cell-mediated target cell lysis.¹⁵³ By presenting two unique antigens, EGFR and EGFRvIII, dual antigen-targeting CAR NK cells enhance the tumor selectivity and specificity. Because glioblastoma exhibits a high degree of antigenic variation, this strategy has been shown to improve tumor specificity and reduce the risk of immune evasion. In targeting many antigens, tumor formation is greatly reduced and survival rates higher according to pre clinic data. For instance, it has been shown that dual antigen-targeting CAR NK cells reduce tumor growth in the murine models of glioblastoma most especially those that are positive for both EGFR and EGFRvIII.¹⁵⁴ Furthermore, these cells have been enhanced with attributes including adenosine synthesis initiated by CD73 that helps to protect the cells from the immunosuppressive factors present in the TME.¹⁵⁵ Because of this defense, CAR-NK cells are able to stay cytotoxic in the challenging TME of glioblastoma.

Adapter CAR (AdCAR) NK cell development is one of the most inventive methods of NK cell-based immunotherapy for glioblastoma. Greater flexibility, tumor selectivity, and stability are made possible by AdCAR technology, which divides conventional CAR components into a dichotomous system consisting of an AdCAR and tumor-specific adaptor molecules (AMs). This method has a number of benefits, including the flexibility to target different tumor antigens during cancer recurrence and the possibility to resume treatment after removing or switching AMs.¹⁵⁶ As linkers, AMs attach themselves to cancer cells and direct AdCAR NK cells to eradicate them. AdCAR systems come in three primary varieties: tag-specific, bispecific, and Fc-binding antibody-binding AdCARs.¹⁵⁷ AdCAR-NK cells utilising biotinylated antibodies as AMs greatly increased glioma cell lysis, notably in cancer stem cells (CSCs).¹⁵⁸ This makes this strategy very flexible and successful for GBM therapy. With this technique, tailored cancer immunotherapy has a versatile and promising option.

Preclinical Animal Models

The utilisation of preclinical animal models has shown to be essential in comprehending the workings of immunotherapy and its effects on glioblastoma.¹⁵⁹ Specifically, mouse models have proven useful in examining the immunological landscape of glioblastoma and in evaluating different treatment approaches. Research employing genetically modified mice (GEMMs) to simulate glioblastoma has shown the intricacy of the TME and its function in generating resistance to immunotherapy.¹⁶⁰ Although there are many different animal models used to research glioblastoma, mice are the subject of the vast majority of preclinical studies.¹⁶¹ Syngeneic models, GEMMs, and xenograft models—which include cell line-based xenografts and patient-derived xenografts (PDX)—are the three main types of mouse models that are commonly used to test developmental therapies and model the biology of GBM.¹⁶² Each type of model has unique benefits and drawbacks. In preclinical models, immune checkpoint blockage has undergone significant testing. In mice models of glioblastoma, for example, it was shown that PD-1 inhibition might result in a large decrease in tumor development; however this was frequently accompanied by enhanced T cell infiltration and activation inside the tumor.¹⁶³ But the immunosuppressive environment of the glioblastoma TME, which is marked by elevated concentrations of Tregs and MDSCs,¹⁶⁴ frequently reduces the effectiveness of these therapies. Preclinical models have also been used to investigate adoptive cell therapy (ACT). Tumor regression has been seen in studies involving the transfer of tumor-specific T lymphocytes into glioblastoma-bearing animals.¹⁶⁵ Significant obstacles are, however, presented by problems including T cell depletion and the loss of specific antigens as a result of immunoediting. For instance, it was shown that T cell treatment significantly increased immunoediting in glioblastoma, which resulted in the tumor’s subsequent immune evasion and the elimination of neoantigens.¹⁶⁶

Immunotherapies in Glioblastoma: Can Immunoediting Overcome the Challenges?

Cancer immunoediting in gliomas has substantial ramifications that should be taken into account when making treatment choices and used to direct the development of new therapies.¹⁶⁷ Current immunotherapies, which rely on boosting immunogenicity through immune response activation and/or the TIME, could effectively drive the cancer immunoediting process by eliminating tumor cells at first, but then making a significant contribution to the positive selection of resistant cancer cells, resulting in tumor escape.¹⁶⁸ Several current immunotherapies for gliomas have failed, and this may be due in part to the fact that the neoantigens they target have been edited out.²² Because of the lack of CD8⁺ T-cells and the preponderance of immunosuppressive macrophages and Tregs in the tumor immune microenvironment, immunotherapies have demonstrated little impact in glioblastoma despite their effectiveness in treating melanoma and non-small cell lung cancer.¹³⁶

Throughout the last decade since its conception, the notion of immunoediting has continued to develop and represents a tractable model for describing the interplay between cancer and the immune system. The terminology of this idea is important because it applies not only to the investigation of underlying molecular and cellular processes in experimental models but also to the application of immunity to the surgical and oncological treatment of cancer patients²⁴ and more importantly, an improved knowledge of glioma immunoediting would surely lead to a more complete view of the gliomagenic program. Apart from that, clarifying the stages of a glioma immunoediting process emphasizes various practical therapeutic approaches, especially in the context of immune escape.²⁴

During the elimination phase, a clear treatment goal is established, and both the critical antigens and the effector cells are studied in more depth. This procedure should give not only the physiologically relevant processes of central nervous system antigen presentation but also the tools essential to attain the goal in looking for successful immunotherapies. In addition, the vaccination tactics of a number of research groups have been concentrated on this field.¹⁶⁹ Moreover, the equilibrium phase may be a therapeutic target if researchers learn more about how immune factors inside the tumor microenvironment keep diseases in a persistent and meta-stable clinical condition.²⁴ Lastly, there is a lot of evidence that shows glioma is successful in the escape phase; it’s not an exaggeration to say that effective immunoevasion is probably crucial to the whole gliomagenic pathway. With the help of the glioma immunoediting framework, scientists may be able to decipher the natural history of the interaction between tumors and the immune system, which could lead to the identification of crucial aspects for immunotherapeutic action as well as the possibility of a cure for the deadly disease.²⁴

Cancer immunoediting may change the antigenome as the tumor progresses in the absence of immunotherapy and this process of cancer immunoediting probably also takes place throughout the treatment.⁸⁹ Anti-PD-L1 treatment changed the mutational environment and reduced the amount of subclonal mutations projected to operate as neoantigens in preclinical studies, indicating potentiated immunoediting.¹⁷⁰ Anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 treatment for NSCLC patients demonstrated changed neoantigen landscapes in many instances of secondary or acquired resistance in 42 patient-matched pretreatment and resistant tumors.¹⁷¹ Most of the mutations that have been eliminated were expected neoantigens, and their eradication was caused by loss of heterozygosity, chromosome deletion areas carrying truncal mutations, or elimination of tumor subclones that expressed neoantigens. According to a different research, ACT could also alter the tumor neoantigen repertoire. Sequential tumor samples and intratumoral T cells from patients who underwent Adoptive cell therapy with both CD8⁺ and CD4⁺ T cells revealed that tumor cells demonstrated loss of numerous T-cell-recognized neoantigens, either by LOH of the mutant allele or decreased expression of the altered genes encoding the neoantigens.¹⁷² This showed immunoediting via the reduction of immunogenic antigen expression, and it was recommended to seek therapeutic induction of widespread neoantigen-specific T-cell responses to prevent immunotherapy resistance. Despite the fact that neoantigens were the focus of the previous research, changes in the production of nonmutant divulged antigens have been noticed noted in the context of immune selection pressure, which can be generated naturally or by vaccination with peptides linked to melanoma that are generated by Melan A/MART-1, tyrosinase, and pmel/gp100.¹²⁵

For the past 15 years, the development on patient outcomes in glioblastoma has been unsatisfactory with only a 5% survival rate after initial diagnosis.¹⁷³ Pre-clinical results of immunotherapy have shown somewhat positive and promising outcomes on glioblastoma; however, the vast majority of immunotherapeutic techniques have failed to show the promised outcomes in large-scale clinical studies.¹⁷ On top of that, there is also no FDA approved immunotherapeutic interventions to address glioblastoma up until now.¹⁷⁴

That being said, knowing how the immune system interacts with glioblastoma is crucial for improving patient outcomes. Apart from that, it is also crucial to take into account and dive deep into the mechanisms of the tumor mediated immune suppression in glioblastoma as it would facilitate the development of novel therapies while the reversal of this impact could also be beneficial to come up with efficacious immunotherapy.²¹ Moreover, it is also essential to consider the concept of immunoediting which assists in the assessment of the process by which the immune system is interacted with cancer cells for shaping the evolution of the tumor.

The whole process of immunoediting is responsible for both sculpting the immunogenic phenotypes of tumors and eliminating those that eventually form in the hosts who are immunocompetent. The concept also states that even though the immune systems have the capability to eradicate the development of cancers, malignant cells with the immunoevasive character might flourish under this selective pressure, allowing the cancer to spread.²⁴ The role of cancer immunoediting in glioblastoma has far-reaching ramifications that should be taken into account when making treatment choices and used to direct the creation of new therapies.¹⁶⁷

It is worth mentioning, that combination therapy tailored to the individual’s tumor profile will indeed help to successfully prevent immune escape from tumors. It is feasible that tumor immuno-evasion systems could be defeated by selecting the most effective therapy regimen at the time of diagnosis.¹⁶⁷ In the future, therapies might well be able to steer tumor development toward a more immunogenic course or overcome CD8⁺ T-cell-mediated immune evasion if researchers have a better grasp on the dynamics of cancer immunoediting. It would also be vital to explore new ways for early identification of glioblastoma since it seems that most of cancer immunoediting is subclinical (while they are still in the elimination or equilibrium phase). By keeping tumor cells in these immunogenic forms, immunotherapies could be used to treat glioblastoma patients.¹⁶⁷

The progress of the review can be assessed by the effective organisation of the three major aspects of immunoediting in glioblastoma: eliminating, equilibrium and escape phase as well as the role of immunoediting in developing effective immunotherapy against glioblastoma. As the notion of immunoediting is groundbreaking because it draws attention to the immune system’s involvement in regulating tumor growth and proposes that the immune system may be co-opted for the purpose of developing novel cancer therapeutics, we suggest further investigation on this topic. With rigorous research, it would be possible to unveil unexplored and undiscovered interconnectedness between tumor environment and immune system in glioblastoma patients as well.

Conclusion

As our knowledge of glioma biology, immune system interactions, and tumor microenvironment grows, so does the evidence that cancer immunoediting plays a crucial role in shaping these tumors. It appears that this process is directly responsible for the immunosuppressive and heterogeneous clinical glioma manifestations that play an important role to their resistance to immunotherapy. In order to harness the immune system’s strength and use it to combat cancer, immunotherapy must first identify suitable targets, and this may be done by learning the principles of immunoediting. The elimination phase of immunoediting could be identified as a therapeutic objective and the equilibrium phase might be considered as a therapeutic target in the development of effective immunotherapy in glioblastoma.

Footnotes

Acknowledgments

A special thanks to Md, Ahasanur Rahman, Dr. SM Rafiqul Islam, Dr. Imteaz Mahmud and the corresponding author Dr. S M Bakhtiar UL Islam for their supervision in the manuscript. Their active involvement and assistance in nurturing the idea and monitoring the progress substantially enhanced the quality of the manuscript. We sincerely thank Madison Blackwell and SaNae Muhammad from Howard University, College of Medicine, for their meticulous language editing and valuable assistance in proofreading the manuscript, ensuring clarity and precision in our work. We would also like to thank Mr. S.M. Sabbir Amin for his active involvement and remarkable support in finalizing the figures.

Author Contributions

T.A., I.M. and S.M.B.U.I. conceived the idea and prepared the outline of the review. T.A., A.H. and N.J. performed the literature search and data extraction, analysis of extracted data and manuscript preparation. MAR, I.M., S.M.R.I. and S.M.B.U.I. supervised the manuscript preparation and prepared the final draft. The authors read and accepted the final version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Statement

ORCID iDs

Tasbir Amin

Imteaz Mahmud

S M Bakhtiar UL Islam

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Immunoediting Dynamics in Glioblastoma: Implications for Immunotherapy Approaches

Abstract

Keywords

Introduction

Immunoediting in Glioma

Phases of Immunoediting

The Elimination Phase

The Equilibrium Phase

The Escape Phase

Cytokine Dysregulation

Immunoediting in Cancer Patients

Immunoediting during Immunotherapy

Immunoediting as a Potential Immunotherapy

Immunotherapy and its Major Challenges

Current Therapeutic Options

Recent Advancements in NK Cell-based Immunotherapy

Preclinical Animal Models

Immunotherapies in Glioblastoma: Can Immunoediting Overcome the Challenges?

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

Ethical Statement

ORCID iDs

References