Advances in research on immune escape mechanism of glioma

Abstract Background Glioma is the most common primary intracranial malignancy in clinical practice, and in particular, IDH‐wildtype glioblastoma has the worst prognosis. In recent years, surgical resection combined with simultaneous radiotherapy and immune checkpoint inhibitors has made some progress, but the efficacy is still not satisfactory, which may be related to the low immunogenicity of glioma cells and the tumor immunosuppressive microenvironment. Methods A comprehensive review of relevant literature was conducted to explore the mechanisms by which tumors suppress antitumor immune responses and produce escape, with a focus on the immune cells in the tumor microenvironment (TME). Results The mechanisms involved in immune evasion of glioma cells are complex and involve with immune cell differentiation and function. Conclusion Our review emphasizes the need for a more profound comprehension of the mechanisms involved in immune response and immune evasion in glioma, to formulate more efficacious treatment modalities.


| INTRODUC TI ON
As the most common primary intracranial malignant tumor in clinical practice, glioma is characterized by short survival period, high recurrence rate, high disability rate, and high mortality rate. 1 Especially, the IDH-wildtype glioblastoma is known as the most malignant, diffused, and aggressive. 2 The main treatments for gliomas are surgery, radiotherapy, and chemotherapy. 3 Surgery is the first step in the treatment of glioma. The boundary of high-grade gliomas is unclear, it is difficult to completely remove the tumor tissue. For patients who progressed to high-grade gliomas like glioblastomas, surgery is often accompanied by further radiotherapy, which includes local radiotherapy and stereotactic radiotherapy. 4 Temozolomide is the most studied chemotherapeutic agent with clear efficacy in the treatment of glioma. 5,6 Also, the vascular targeting agent bevacizumab was found to be effective in recurrent high-grade gliomas. 7 Despite of this, the overall survival (OS) rate of gliomas has not been significantly improved. It is necessary and urgent to develop new treatments and approaches for glioma as a malignant tumor.
Tumor microenvironment refers to the occurrence, growth, and metastasis of tumors, which are closely related to the internal and external environment of tumor cells, including not only the organizational structure, function, and metabolism of tumors but also the internal environment of tumors themselves. Tumor is closely related to its surroundings and its own environment, both of which are interdependent and antagonistic. Tumor cells can improve the conditions of development by self-secretion and promoting paracrine secretion.
The whole body and local tissues can also be changed by means of immunity, secretion, and metabolism to limit and affect the development of tumors, which is a very complex process. The biological processes in tumor microenvironment related to cancer malignant progression was shown in Figure 1. Immunotherapy is currently the most active and prospective research direction in the domain of tumor treatment.
Immunotherapy is to stimulate the body's immune cells to respond to tumors by enhancing the function of immune effector cells, in order to achieve the purpose of removing tumor cells. 8 Years of basic research on tumor immunity have been accumulated, and a mass of tumor immunotherapy has recently entered the clinical trial stage. Tumor immune escape stated for the phenomenon that tumor cells evade the recognition and attack of immune cells and immune molecules through various mechanisms, so that they can continue to grow and metastasize in the organism. 9 Whereas, some malignant tumor cells will escape from the immune system and flee from the immune system. 10 Therefore, the occurrence of immune escape by tumor cells is a vital strategy for tumor survival and progression. Numerous factors can contribute to the phenomenon of immune escape in tumor cells.
These include mechanisms such as the shielding of tumor-specific antigens, the removal of targets recognized by the body's immune system, a decrease in the population of immune cells capable of effectively killing tumor cells, an increase in immunosuppressive cells that facilitate tumor immune evasion, and an upregulation of immunosuppressive factors within the tumor microenvironment (TME). 11 Immunosuppression is a key aspect of the mechanism by which tumor cells evade immune surveillance. One such mechanism involves the secretion of immunosuppressive cytokines by tumor cells, which promote the differentiation and proliferation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), leading to the manifestation of potent immunosuppressive effects. 12 Within the tumor microenvironment, myeloid-derived suppressor cells (MDSCs) may differentiate into tumor-associated macrophages (TAMs), or they may directly suppress the activity of cytotoxic T lymphocytes (CTLs) or induce T cell inactivation, thereby promoting the establishment of an immunosuppressive milieu. 13 The immune cells involved in tumor immunosuppression was displayed in Figure 2.
Investigations into the existence of lymphoid structures within certain regions of the brain tissue challenge the conventional notion of the central nervous system (CNS) as a partially immunologically privileged site, indicating that these structures can effectively and promptly clear foreign antigens or senescent and mutated cells. 14 The ability of glioma cells to elude the host's immune surveillance arises from their low immunogenicity, elevated secretion of immunosuppressive factors, absence of adhesion and costimulatory molecules, and heightened presence of immunosuppressive cells within the tumor microenvironment. 15 In this manuscript, we go over the researches on the mechanisms of immune response and immune escape of tumor cells in glioma to provide a reference for exploring and developing more effective immunotherapeutic options.

| THE OVERVIE W OF G LI OMA TUMOR IMMUNE MICRO ENV IRO NMENT
The glioma microenvironment pertains to the intrinsic and extrinsic surroundings that are intricately linked to the onset, progression, and F I G U R E 1 The biological processes in tumor microenvironment related to cancer malignant progression. The biological processes related to cancer malignant progression in the tumor microenvironment mainly include fibroblast recruitment and activation, epithelial mesenchymal transition, angiogenesis and immune evasion. Created with BioRe nder.com. metastasis of glioma, encompassing the tissue's structure, function, and metabolism in which the tumor cells reside, as well as the inherent milieu of the glioma cells themselves, which includes both the nucleus and cytoplasm. 16 Tumor cells need to consume large amounts of nutrients to meet their metabolic needs, and the plasticity of tumor metabolism allows them to better adapt to a depleted or changing nutritional environment, which in turn reshapes the tumor immune microenvironment. 17 The tumor immune microenvironment is divided into antitumor immune microenvironment and pro-tumor immune microenvironment. 18 The glioma-associated microglia in the tumor microenvironment, the pro-tumor effects of macrophages (GAMs), Treg, and the inactivation of natural killer (NK) cells can all diminish the antitumor influences of the organism and are closely linked to the constitution of the glioma immunosuppressive microenvironment. 19 Gliomas have a unique immune microenvironment infiltrated by two main types of immune cells, microglia, and tumor-associated cells (TAM, mainly M2-type tumor-promoting macrophages). 20 They not only play the role of phagocytosis of tumor cells but also perform antigen presentation and secrete some inflammatory factors. After tumorigenesis, the inhibitory microenvironment leads to a decrease in phagocytosis and antigen-presenting functions of both cells and promotes TAMs to M2 polarization, among others. 21 And both cells express PD-L1 on their surface, and they both induce a decrease in T-cell activity through the mechanism of immune check sites. They also express PD-1 on their surface, which inhibits their phagocytosis and antigen-presenting ability by binding to PD-L1 ligands on tumor cells, etc. 22 TILs are the main antitumor cells, but in glioma, the existence of the blood-brain barrier causes difficulties in the recruitment of T cells. Not only the number of TILs is low but also the presence of receptors such as PD-1 and CTLA4 on TILs can inhibit their antitumor effects after binding to ligands such as PD-L1 and CD86 on tumor cells. 23 And nowadays, the application of immune checkpoint locus inhibitors can help restore the function of killer T cells within the tumor, which in turn can perform tumor-killing function. Dendritic cells (DCs) are specialized antigen-presenting cells that accomplish antigen presentation and activation of T cells mainly in the brain or deep cervical lymph nodes, but the immune microenvironment of glioma suppresses the function of DC cells. 24 Also, there are two suppressor cells in glioma, Treg, and MDSC, which are closely related to PD-L1 expression in tumor cells. 25 Cells within the microhabitat of glioma stem cells (GSCs) secrete a variety of cytokines to stimulate glioma stem cell self-renewal, induce angiogenesis, and recruit immune cells to promote tumor cell invasion and metastasis. 26 Microhabitat is a specialized microenvironment that can be regulated by regulating tumor stem cells (TSCs) both in the form of direct intercellular contact and secretion of cytokines. 27 Among tumor microenvironments (TME), microhabitat is an anatomically unique microenvironment. Glioma-induced cells have high adaptability, high plasticity, strong self-renewal capacity, unlimited proliferation capacity, and multidirectional differentiation potential, which are properties that allow them to survive under adverse conditions and suggest that the stem cell microenvironment is necessary to maintain stem cell properties, metabolic plasticity. 28 There is a strong link between F I G U R E 2 Immune cells involved in tumor immunosuppression. Many immune cells can participate in the process of tumor immunosuppression by interacting with tumor cells. These cells mainly include MDSC, M2, ILC2, N2, NK2, Th2, Treg, and NKT2. Created with BioRe nder. com. glioma stem cells and the microenvironment in which they live. In the stem cell microenvironment, glioma stem cells can induce differentiation of bone marrow-derived monocytes and microglia into TAMs, the latter being the major inflammatory cell population in the TME. 29 Multiple lines of evidence suggest that TAMs have a role in promoting tumorigenesis, growth, invasion, and metastasis, affecting tumor metabolism. 30,31 Microhabitat maintains the essential properties of glioma stem cells, maintaining their phenotypic plasticity and thus allowing them to effectively evade surveillance by the immune system. 32 Recently single-cell analysis has emerged as a powerful tool to study the heterogeneity of gliomas at the single-cell level and to identify the cellular and molecular mechanisms involved in immune escape. 33 Single-cell RNA sequencing (scRNA-seq) has been used to identify different subpopulations of glioma cells and to characterize their gene expression profiles. 34 This has led to the identification of novel immune checkpoint molecules and immunosuppressive pathways that contribute to glioma immune escape. 35,36 In addition, single-cell analysis has also been used to study the immune microenvironment of gliomas, including the infiltration of immune cells and their functional states. 35 Furthermore, single-cell analysis has provided insights into the dynamic changes in the immune microenvironment during glioma progression and in response to immunotherapy. 37 Overall, single-cell analysis has significantly advanced our understanding of the complex immune escape mechanisms in gliomas and has provided potential targets for novel immunotherapeutic strategies.

| CHAR AC TERIS TI C S OF THE COMP ONENTS OF THE G LI OMA IMMUNE MICRO ENV IRO NMENT INVOLVED IN THE IMMUNE E SC APE MECHANIS M
The glioma immune microenvironment is composed of various immune cells and factors that interact with the tumor and play a critical role in tumor progression and response to therapy. Immune escape mechanisms are a significant challenge in glioma treatment, and the involvement of different immune components in these mechanisms has been extensively studied. (Figure 3). prognosis, but the specific immune effects also take into account the infiltration characteristics of the immune cells, that is, type, location, number, cell ratio, etc. 44 The process of T cell activation was displayed in Figure 4.

| Tumor-infiltrating T lymphocytes and immune escape
Tumor-infiltrating T lymphocytes also have an important role in the immune escape of glioma (Table 1). Studies have shown that miR-21 expression is significantly increased in both glioma cells and tissues.
Inhibition of miR-21 inhibited the growth, migration, and invasion of glioma cells and accelerated apoptosis, and increased CD8+ T proliferation and cytotoxic activity. In addition, miR-21 is also enriched in BMDM exosomes and can be delivered to glioma cells to promote immune escape by inhibiting PEG3 expression. 45

| Tumor-associated macrophages and immune escape
Monocytes are recruited by chemokines, cytokines, and growth factors generated by tumor cells or mesenchymal cells and further differentiated to produce tumor-associated macrophage. 59  factorβ (TGFβ), and glucocorticoids. 65 Based on extensive studies, it is proposed that TAM in TME is mostly polarized to anti-inflammatory macrophages (M2 phenotype), which have the potential to elevate the activity of IL-10, TGFβ, and hyperarginase-1, and stimulate the expression of cell surface markers, in addition to promoting tumor angiogenesis, growth, and expression of various immunosuppressive cytokines. 66 This is in contrast to most pro-inflammatory mediators secreted by M1 macrophages, including TNFα, IL-1b, and IL-12. 67 Tumor-associated macrophages also have a vital role in immune escape in gliomas (Table 2 Under physiological conditions, the normal function of NK cells is regulated and conditioned by both activating and inhibiting signals. 73 However, some tumor cells can cause changes in NK cell function through different regulatory mechanisms that prevent them from performing their normal immunosurveillance function, resulting in tumor cells evading immunosurveillance. 74 The approaches for NK Cell Immunotherapy were displayed in Figure 5. Natural killer also has an important role in immune escape from glioma ( Table 3 83 antigen-presenting cells in the body and can directly activate Th and CTL in the immune system, as well as cause B cells to produce antibodies. 77 Tumor antigen-sensitized DCs in vitro were obtained by isolation and purification of DCs, which can lead to T cell activation through high levels of stimulation of MHC class I and MHC class II molecules. 78 Also, DCs can induce the secretion of IFNα, IFNγ, IL-3, IL-12, and other factors to produce relevant immune responses. 79 In addition, DCs can be genetically engineered to enhance the antitumor immune response. 80 Dendritic cells also have an important role in the immune escape of gliomas (Table 4)

| FUTURE PROS PEC TS AND DISCUSS ION
The fundamental of tumor treatment is the capability of the body's immune system to recognize and distinguish normal cells from diseased cells, and to specifically recognize, kill, and remove tumor cells by recognizing antigens on the surface of tumors. 88 In addition to surgical treatment, radiotherapy, and chemotherapy, there is also a growing interest in immunotherapy, including PD-L1/PDL2-PD-1, and related signaling pathways, CTLA-4 inhibitors and CAR-T therapy. 89,90 However, CAR-T treatment still has many shortcomings. The limitations of CAR-T therapy were showed in Figure 6. Immunotherapy is currently one of the most attractive therapeutic strategies for cancer patients.
An increasing number of recognized immune checkpoint inhibitors (including PD-1 and CTLA4 inhibitors) affect the local tumor immune environment by blocking the PD-1/PD-L1 and CTLA4 signaling pathways and have been used to treat certain types of cancer. 91,92 The phenomenon that tumor cells use all kinds of mechanisms to escape the surveillance and attack of the body's immune system so that they can continue to grow and metastasize is called tumor cell immune escape, which is a crucial strategy for tumor survival and progression. 93 In TME, In summary, immunotherapy has improved the treatment of many patients with previously poor prognosis of solid tumors but has not shown significant efficacy in the treatment of glioma. In this paper, we reviewed the research on immune response mechanism and immune escape mechanism of tumor cells in glioma, with the aim of providing reference for the subsequent therapeutic research.

CO N FLI C T O F I NTE R E S T S TATE M E NT
We declare that we have no financial or personal relationships that could inappropriately influence or bias the content of this article.
Additionally, we have no conflicts of interest, including but not limited to commercial, personal, political, intellectual, or religious interests, that could be perceived as influencing this work. This manuscript represents original research and has not been previously published, nor is it under consideration for publication elsewhere.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.