Glioma immunotherapy: Cholesterol metabolism of central nervous system

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Cholesterol metabolism in central nervous system and its effect on immunotherapy of glioma

Glioma immunotherapy: Cholesterol metabolism of central nervous system. Glioma is the most common primary malignant tumor of the central nervous system, of which glioblastoma multiforme (GBM) has the highest degree of malignancy. Glioma may originate from neural stem cells, glial progenitor cells or astrocytes, etc.

The standard treatment plan for glioma is: comprehensive treatment combining the widest range of precision surgery to remove the tumor, radiotherapy, and chemical (temozolomide) treatment. Currently, the median survival time of treated patients is approximately 14.6 months.

The Cancer Genome Atlas (TCGA) analysis shows that the occurrence of GBM is closely related to the gene changes of RTK/phosphoinositol 3-kinase [phosphoinositol 3-kinase (PI3K)]/MAPK, p53 and Rb signal transduction pathways.

However, the clinical application of targeted drugs targeting these pathways in the treatment of glioma failed to achieve breakthrough results. The complexity of signal transduction pathways, the heterogeneity of tumor cell genomes, and the blood-brain barrier (BBB) ) Are all possible reasons for poor efficacy.

Cholesterol is a small-molecule lipid substance widely found in animals and is essential for maintaining cell activity and function. Cholesterol metabolism can produce a variety of biologically active intermediates by activating multiple signaling pathways, the latter can regulate multiple signaling pathways, and play a role in regulating cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement, and cell membrane homeostasis. Important role. Cholesterol not only participates in the metabolic pathway of glioma, but also plays an important role in the formation and treatment of glioma as a carrier of targeted drugs.

1. Central Nervous System and Cholesterol

Cholesterol is an important part of cell membranes and plasma lipoproteins, and is the precursor of steroid hormones, bile acids and hydroxycholesterol, which is oxysterol. The cholesterol-rich microdomains on the cell membrane are essential for transmembrane signal transduction. At the same time, cholesterol itself and its oxidation products can also act as signal molecules.

Changes in lipid metabolism can affect cell growth, proliferation, differentiation and migration. There is evidence that in tumor diseases such as prostate cancer, the initiation of cell proliferation is more dependent on lipid metabolism than glycolysis. In the central nervous system, cholesterol is mostly located in the myelin sheath. At the same time, cholesterol is also the main component of synaptic vesicles, which is essential for their formation and function. With the gradual deepening of research, industry scholars have discovered that cholesterol is involved in the formation of neuronal dendrites and axons, the survival of neurons, the proliferation of astrocytes, nerve repair and remodeling, and the transmission of signal pathways related to neurodevelopment.

Under normal circumstances, the cholesterol concentration in the brain is maintained within a certain range, that is, brain cholesterol homeostasis, which is of great significance for maintaining the normal function and development of the central nervous system. The cholesterol homeostasis in glioma cells is affected by cholesterol uptake, synthesis and external Dynamic control of platoon and many other aspects.

1.1 Sources of Cholesterol in the Brain

Cholesterol content in the brain accounts for 23% of all cholesterol in the human body. It plays a vital role in maintaining the integrity of cell membranes, myelination, synapse formation and neurotransmission. Due to the presence of BBB, little or no cholesterol can be transported from the peripheral circulation to the central nervous system. Therefore, the cholesterol needed by the brain is basically derived from endogenous synthesis, and neurons can produce most of the cholesterol needed for their own growth and synapse formation. When the neuron matures, the function of the neuron to synthesize endogenous cholesterol is gradually replaced by astrocytes and oligodendrocytes.

1.2 Cholesterol metabolism in the brain

In stark contrast to cholesterol, hydroxy cholesterol has the ability to cross the blood-brain barrier and enter the brain. The excess cholesterol in the brain is mainly hydroxylated by Cholesterol 24-hydoxylase (CYP46A1), a member of the cytochrome P450 (CYP) family, to form 24(S)-hydroxycholesterol (OHC). 24(S)-OHC has the ability to cross the BBB and plays an important role in brain cholesterol metabolism. 24(S)-OHC is secreted into the peripheral circulation via the BBB, and is metabolized in the liver by binding to low-density lipoprotein for transport. CYP46A1 is the key rate-limiting enzyme in this pathway, as well as a brain-specific enzyme and a specific indicator of cholesterol oxidation.

The activity of CYP46A1 directly affects the content of 24(S)-OHC in the brain, and can also catalyze the formation of a small amount of 20(S)-OHC and 27(S)-OHC. 90% of the 24(S)-OHC in the human body comes from the brain, which can more accurately reflect the metabolic level of cholesterol in the brain. Studies have shown that 24(S)-OHC has neurotoxic effects, which can overload intracellular calcium by generating too many free radicals and induce neuronal apoptosis in vitro. Therefore, 24(S)-OHC can also be used as a peripheral biological indicator of neurological diseases.

Binding with apolipoprotein E (ApoE) is another metabolic pathway of cholesterol in the brain. ApoE is an important cholesterol carrier protein in the brain. It is synthesized and secreted by astrocytes in the brain tissue. It exists on the surface of various lipoprotein particles and acts as a ligand in the removal of chylo particles and very low-density lipoproteins. On the one hand, ApoE acts as a transport carrier to help cholesterol pass through the BBB; on the other hand, it can cooperate with cholesterol and myelin to maintain and repair damaged nerve cell membranes. In addition, steroid hormone synthesis acute regulatory protein (steroidogenic acute regulatory protein, StAR) transport pathway, ATP-binding cassette transporter A1 (ATP-binding cassette transporter A1, ABCA1) induction pathway, cholesterol acyl transferase 1 (acyl-CoA: cholesterolacyl transferase 1) ,ACAT1) pathways are also involved in the synthesis of related cholesterol in the brain.

StAR can guide the transport of free cholesterol in neurons to the inner mitochondrial membrane to form pregnenolone, the common precursor of a variety of neurosteroids, and it can also promote the synthesis of bile acids to facilitate cholesterol excretion. As a membrane protein, ABCA1 can regulate the reverse rotation of cholesterol and phospholipids into cholesterol, and promote the formation of ApoE-cholesterol-phospholipid complex. And ACAT1 can catalyze free cholesterol to generate cholesterol ester, and affect cholesterol metabolism by controlling the dynamic balance between free cholesterol and cholesterol ester in the cell. ACAT1 is the only enzyme in the cell that catalyzes the synthesis of cholesterol ester from free cholesterol. Knockout of ACAT1 to reduce cholesterol ester synthesis can significantly alleviate the progression of glioma lesions in the mouse model.

2. The role of cholesterol metabolism in glioma

A variety of neurological diseases are closely related to abnormal brain cholesterol metabolism. Alzheimer’s disease (AD), epilepsy, Parkinson’s disease (PD) and other diseases have been confirmed to be induced by the destruction of brain cholesterol homeostasis . More and more evidences show that cholesterol metabolism disorders are related to the development of a variety of cancerous diseases including GBM, but its role in disease progression is still unclear. However, there are conflicting epidemiological data on the relationship between serum cholesterol levels and cancer risk, indicating that circulating cholesterol levels only have a marginal effect on cancer development. OHC is a hydroxylated derivative of cholesterol, which plays an important role in lipid metabolism, and has received wide attention as a compound that activates signals and induces mutations.

2.1 Cholesterol metabolism and glioma development

Cholesterol metabolism plays an important role in the proliferation, migration and invasion of tumor cells. Eliminating cholesterol or hindering cholesterol transport can inhibit the growth and invasion of many tumors. Compared with normal cells, the cholesterol synthesis of tumor cells is increased, and lipid metabolism disorders are one of the characteristics of malignant tumors. In mammals, cholesterol homeostasis is strictly regulated by a complex protein network centered on cholesterol regulatory element binding proteins (sterol-regulatory element binding proteins, SREBPs) and liver X receptors (LXRs). These transcriptions Factors are involved in the inflow, outflow, synthesis, metabolism and esterification of cholesterol.

SREBPs are a class of membrane-bound transcription factors that can regulate cholesterol homeostasis in the human body and activate the expression of some genes involved in cholesterol synthesis. SREBPs mainly exist in three forms, including SREBP-2 which is mainly involved in cholesterol synthesis, SREBP-1c which mainly stimulates fatty acid synthesis and SREBP-1a which preferentially activates cholesterol synthesis. SREBP-2 can promote gene transcription to generate 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAreductase, HMGCR) and low-density lipoprotein receptor (LDLR), etc., and then regulate Cholesterol synthesis and intake. HMGCR is the rate-limiting enzyme of the cholesterol synthesis pathway, and the raw material supply for the synthesis of cholesterol is regulated by LDLR. HMGCR and LDLR gene transcription will change according to changes in cholesterol levels in the cell.

The survival of glioblasts is closely related to cholesterol, and the expression of SREBP2 and synthetases in glioma tissues is up-regulated. Some studies believe that SREBPs are related to epidermal growth factor receptor (EGFR) mutations and PI3K overactivation. SREBPs can promote the growth of GBM, but analysis using the cancer genome atlas (TCGA) database shows that, Diffuse glioma SREBP2 high expression group and low expression group have a better prognosis. When there is too much cholesterol in cells, LXRs can induce E3 ubiquitin ligase to promote cholesterol efflux and decrease LDLR by inducing the up-regulation of ABCA1 and ABCG1 gene expression.

These transduction pathways are targeted and have been proven to be effective strategies to inhibit the growth of GBM in animal model studies. Cholesterol metabolites, including cholesterol esters and OHC, are also elevated in tumor cells. Excess cholesterol in the brain can be metabolized into OHC through enzyme catalysis or direct oxidation, including 24(S)-OHC, 25-OHC, 27-OHC, 22-OHC, 7-OHC, etc. 24(S)-OHC, 25-OHC, 27-OHC and 7α,25-OHC these important oxidized cholesterols are closely related to immune diseases. In addition to participating in cholesterol metabolism, OHC can also regulate signaling pathways such as Hedgehog, Wnt, and MAPK.

Cholesterol-25-hydroxylase (CH25H) is a member of the lipid desaturase and dehydrogenase family, as a key enzyme to hydroxylate cholesterol to form 25-OHC, which is then further hydroxylated by CYP7B1 7α, 25-OHC, and then combine with nuclear receptor family such as LXRs to play a wide range of effects. OHC is the ligand of LXRs. The latter inhibits the SREBPs pathway to reduce cholesterol synthesis, and at the same time activates ABCA1 to promote the excretion of cholesterol from the cell, which may help inhibit tumor growth. 25-OHC and 7α, 25-OHC are synthesized by a variety of cells in lymphoid tissues and non-lymphoid tissues, and can be up-regulated by inflammatory response stimulation. They have the function of recruiting and chemotaxis immune cells, and are used in inflammation, immunity, antiviral and tumor Play an important role in the occurrence and development of

Enzymes required in the 25-OHC synthesis pathway are found to be up-regulated in macrophages and dendritic cells (DCs) exposed to inflammatory mediators, suggesting that 25-OHC may have a wide range of effects in the immune system . The effects of 25-OHC and 7α, 25-OHC depend on inflammatory and immune cell membrane receptor G protein-coupled receptor 183 (Gprotein-coupled receptor 183, GPR183), which is Epstein-Barr virus-induced receptor 2 (Epstein-Barr virus-induced GPR183). -protein coupled receptor2, EBI2). In vitro experiments have found that different tumor cells can recruit neutrophils through the CXCR2 pathway by expressing 22-OHC.

In glioma cells, inducing the up-regulation of CH25H expression increases the synthesis of 25-OHC, which can have a chemotactic effect on monocytes/macrophages, and this effect is mediated by the EBI2 receptor. Studies have shown that GBM cells express CH25H at the mRNA and protein levels through cytokine induction, and can synthesize and secrete 25-OHC. Studies have found that exogenous 25-OHC and lipid extracts derived from GM133 conditioned medium can induce THP-1 cell migration through EBI2. Moreover, human peripheral blood mononuclear cells can also migrate in response to exogenous 25-OHC. Therefore, 25-OHC produced by GBM cells may be one of the chemotactic signals that induce the recruitment of monocytes to tumor cells, and can promote the deposition of tumor-associated macrophages.

In addition, 25-OHC was found to antagonize the replication of multiple viruses through lipid synthesis and separation, regulate the synthesis of immunoglobulin A, promote the formation of macrophage foam cells, and upregulate some inflammatory cytokines such as interleukin (interleukin IL). )-6 and mediate feedback inhibition of IL-1 family cytokine production. EBI2 is a type of 7-pass transmembrane receptor, which is expressed on the cell membrane of immune cells such as B cells, T cells, dendritic cells, and monocytes and macrophages. EBI2 can mediate the transfer of B cells from central follicles to peripheral follicles and the production of antibodies in lymph nodes. The chemotaxis of immune cells will affect the immune situation of the tumor site, providing a new way to promote the immune response of the tumor site and avoid immune escape. Ideas.

Studies suggest that the specific mechanism of chemotactic B cell metastasis may be the different distribution of metabolic enzymes such as CH25H and CYP7B1 in the stromal cells of different regions of the lymph node, which in turn leads to the formation of a concentration gradient of 7α and 25-OHC in different regions. Some studies have found that 7α 25-OHC is the ligand with the strongest agonistic effect of EBI2. Therefore, the chemotactic effect of EBI2 on B cells is proportional to the concentration of 7α,25-OHC and its precursor 25-OHC. The hydroxysterol-EBI2 signaling pathway directs the distribution of B cells in lymph nodes. In addition to B cells, this type of chemotaxis is also reflected in the regulation of the immune function of spleen CD4+DC and T cells.

Since DCs in the marginal area of ​​the spleen can present antigens in the blood, the number of CD4+DCs in the marginal area of ​​the spleen of mice lacking EBI2 or 7α,25-OHC synthesis system is significantly reduced, which further affects the activation of helper T cells and the production of antibodies process. In addition, it can regulate the interaction of CD4+ T cells with DCs in lymphoid tissues. CD25 produced by DCs can inhibit the inhibitory effect of IL-2 on the differentiation of CD4+ T cells and promote the differentiation of CD4+ T cells. In addition, 7α,25-OHC was also found to be the guiding signal of EBI2+DC.

The above studies have shown that OHC represented by 7α,25-OHC can have chemotaxis and migration effects on immune cells expressing EBI2 receptors. EBI2 and 7α,25-OHC deficiency may cause immune response defects. 27-OHC may be a sensitive regulator of cholesterol metabolism, which can inhibit cholesterol synthesis and stimulate cholesterol transport in astrocytes. Previous studies have proved that 27-OHC is a concentration-dependent inhibitor of low-density lipoprotein uptake, degradation and HMGCR intracellular mediator. It was also found that the inactivation of HMGCR was caused by the conversion of cholesterol to 27-OHC.

Studies have found that 27-OHC can reduce the level of cholesterol in glioma cells by down-regulating the expression of SREBP-1a, HMGCR and LDLR, and by up-regulating the perxisome proliferators-activated receptor (PPAR)- The gene expression of γ, LXR-α, ABCA1 and ApoE promotes cholesterol transport, resulting in a significant decrease in viability and even apoptosis of glioma cells treated with 27-OHC. In addition, studies have shown that 27-OHC can inhibit the growth of prostate cancer by depleting intracellular cholesterol levels.

Other studies have found that 27-OHC in breast cancer cells induces epithelial mesenchymal transition (EMT) to accelerate tumor growth, and this phenomenon also occurs in some subtypes of early hepatocellular carcinoma. At the same time, circulating lipoproteins related to the transport of 25-OHC, 24(S)-OHC and 27-OHC may be essential for the formation of gliomas, such as high-density lipoproteins.

High-density lipoprotein contains sphingosine-1-phosphate (sphingosine-1-phosphate) is a kind of highly effective GBM cell division agent, which can participate in the induction of increased DNA synthesis in glioma cells, and extracellular regulated protein kinase (extracellular regulated protein kinase). kinases, ERK) phosphorylation and Ca2+ activation.

2.2 Cholesterol metabolism and tumor microenvironment

The tumor microenvironment is the internal environment in which tumor cells produce and live. In recent years, the concept of tumor microenvironment has gradually improved. It is defined as a heterogeneous mixture of cells rich in non-tumor cells, glioma stem cells, tumor cells, immune cells, and stromal cells. These cells are contained in a modified Extracellular matrix. Among them, immune cells include myeloid suppressor cells, tumor-related microglia/macrophages, CD4+T helper cells, cytotoxic CD8+T cells, natural killer cells, regulatory T cells, and dendritic cells. Antigen-presenting cells such as cells and myeloid macrophages.

The growth and metabolism of tumors need to consume a lot of nutrients, leading to interaction and remodeling of the nutritional environment. The lipid metabolism of most tumor cells is abnormally enhanced, while fatty acid decomposition slows down. Glioma stem cells mainly regulate lipid metabolism by influencing related enzymes in the process of fatty acid oxidation. For example, carnitine palmitoyltransferase 1A (CPT1A) has the ability to regulate the transport of long-chain fatty acids to mitochondria, while CPT1C is a regulator of fatty acid β oxidation. Glioma stem cells regulate CPT1A and CPT1C to regulate glial. Energy metabolism of tumors. Studies have shown that both CPT1A and CPT1C are highly expressed in glioma patients, and CPT inhibitors can inhibit the proliferation of glioma stem cells when acting on glioma stem cells.

2.3 Cholesterol metabolism and treatment of glioma

With the gradual deepening of tumor metabolism research, anti-tumor drugs based on key enzymes or transporters in the metabolic pathway have begun to become new tumor treatment options. For example, indoleamine 2,3-dioxygenase was first used in tumor immunotherapy, and indoleamine 2,3-dioxygenase inhibitors combined with chemotherapy or other immunotherapy are manifested in diseases such as melanoma A certain survival benefit. In addition, researches on immunotherapy based on amino acids and glycolytic metabolism are also abundant. The former is represented by the regulation of glutamine metabolism, and the latter mainly focuses on targets such as hexokinase and lactate dehydrogenase.

In the immunotherapy of lipid metabolism regulation, the ACAT1 inhibitor avasimibe has good anti-tumor ability. This is because the inhibition of cholesterol esterification increases the plasma membrane cholesterol level of CD8+ T cells, leading to T cell receptors The enhancement of clustering and signal transduction and the effective formation of immune synapses enhance the anti-tumor activity of CD8+ T cells. Research suggests that the combination therapy of avaimibe and PD-1 drugs has more significant clinical significance than the monotherapy of PD-1 drugs. The combination of cholesterol metabolism inhibitors and tumor vaccine immunotherapy also has certain clinical prospects.

In animal models of lung cancer with Kras mutations, avaimibe combined with Kras peptide vaccines can significantly reduce the number of regulatory T cells (Treg) to promote tumor infiltration of CD8+ T cells. In addition, ACAT1 inhibitors K604 and ATR-101 have also been experimentally confirmed to effectively inhibit tumor growth in some xenograft models. Compared with normal brain tissue, the level of CYP46A1 in GBM specimens was significantly reduced. The decrease of CYP46A1 expression is related to the increase of tumor grade and poor prognosis of human glioma. CYP46A1 overexpression inhibits cell proliferation and inhibits tumor growth in vivo by increasing 24(S)-OHC levels and reducing cholesterol accumulation. At the same time, it was found that GBM cells treated with 24(S)-OHC can inhibit tumor growth by regulating the signal transduction of LXRs and SREBPs.

The anti-HIV drug efavirenz is a known CYP46A1 activator that can penetrate the BBB and inhibit the growth of GBM by activating the CYP46A1/24-OHC axis in the body. Research suggests that CYP46A1 is a key regulator of GBM cell cholesterol, and CYP46A1/24-OHC axis is a potential therapeutic target. Studies have found that isocitrate dehydrogenase (IDH) mutations can promote the production of 24(S)-OHC and change the cholesterol homeostasis in glioma tissue.

IDH mutation is one of the most important genetic changes in low-grade gliomas and secondary GBM, and is even used to guide the classification of gliomas. Many evidences indicate that IDH mutations are related to tumor metabolic reprogramming and may be potential targets for tumor therapy. In addition to promoting glutamine addition and glycolysis, IDH mutations also hinder lipid synthesis by reducing the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and acetyl-CoA.

CYP46A1 has been confirmed to have increased expression in IDH1 mutant astrocytes and glioma cells, which promotes the production of 24(S)-OHC, and reduces cholesterol in the brain by reducing cholesterol influx and increasing cholesterol outflow. The reduction of cholesterol levels feedback stimulates its biosynthesis, making IDH1 mutant glioma cells more sensitive to the known HMGCR inhibitor atorvastatin, which was previously thought to have a certain anti-tumor effect. In addition, studies have found that adding atorvastatin can cause significant IDH1 mutant glioma cell death and migration inhibition.

Clinical studies have found that the combined treatment of lovastatin and temozolomide has a relatively obvious anti-glioma cell growth effect, and has the potential as an adjuvant treatment strategy for glioma. As mentioned earlier, activating LXR can increase cholesterol efflux and reduce cholesterol uptake, which is also a potential anti-tumor strategy. Studies have shown that synthetic LXR agonists GW3965 and T0901317 can significantly inhibit tumor growth in animal models of glioma, breast cancer and prostate cancer. In addition to activating LXRs, LXR-623 also has a high degree of brain permeability, which can selectively kill glioma cells and prolong the survival time of GBM mice.

3. Outlook

Glioma is the most common primary malignant tumor of the central nervous system, with short survival time, high recurrence rate and high mortality rate. At present, the combined treatment effect of precision surgery, radiotherapy and chemotherapy is not satisfactory. Therefore, it is necessary to continue to explore new treatment strategies for glioma. Immunotherapy has been a research hotspot in the field of tumors in recent years. Immunotherapy including immunosuppressants, tumor-specific vaccines, adoptive cell therapy, oncolytic viruses, etc. has progressed rapidly. It has been used in non-small cell lung cancer, melanoma, kidney cancer and the blood system The treatment effect in malignant tumors is remarkable.

Due to the existence of the special microenvironment of gliomas, compared with extra-brain tumors, the efficacy of immunotherapy in gliomas is still not ideal. Over the years, researchers in the industry have gradually realized that tumor-related cell metabolism should no longer be limited to changes in glycolysis and the tricarboxylic acid cycle. Cholesterol metabolism can produce a variety of biologically active intermediates, which are produced by activating multiple signaling pathways, and can also regulate multiple signaling pathways. They are used to regulate cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement and cell membranes. Stability and other aspects play an important role. The brain is an important organ rich in lipids, and the deep connection between cholesterol metabolism and glioma is worthy of further exploration.

(source:internet, reference only)

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