The influence between the metabolic reprogramming of tumor and immune cells is one of the recognized determinants of tumor immune response. Growing evidence suggests that tumor metabolism not only plays a key role in maintaining tumorigenesis and survival, but can also influence immune molecules (such as lactate, PGE2, arginine, etc.) by releasing metabolites. Indeed, this energetic interaction between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting the efficient supply of nutrients, and leading to microenvironmental acidosis, which impedes immune cell function. More interestingly, metabolic reprogramming is also essential in maintaining the homeostasis of various types of immune cells in the body. Currently, a growing body of research indicates that immune cells undergo metabolic reprogramming during proliferation, differentiation, and execution of effector functions, which are critical for immune responses. Therefore, understanding how the metabolic reprogramming of tumor cells and immune cells modulates anti-tumor immune responses may enable us to find therapeutic approaches targeting metabolic pathways in anti-tumor immunotherapy.
Tumor cell metabolism
Reprogramming of energy metabolism promotes rapid cell growth and proliferation by regulating energy metabolism and is considered to be a unique hallmark of tumor cells. Since tumors are a heterogeneous disease, their cellular and structural heterogeneity endow them with complex metabolic patterns.
In fact, tumor cells mainly use the glycolytic pathway to rapidly provide ATP for their own growth, and also provide biological macromolecules for cell replication through the pentose phosphate pathway (PPP) and the serine metabolic pathway. Even in the presence of abundant oxygen, tumor cells preferentially utilize glycolysis to generate ATP, which is known as aerobic glycolysis (Warburg effect).
At the same time, tumor cells not only decompose glucose to provide ATP, but also use glutamine, serine, arginine, fatty acids and lipids to promote their own proliferation. Interestingly, tumor cells choose different metabolic methods to generate ATP and biomacromolecules for their own use according to the concentration of external nutrients and different stress conditions.
For example, under the stress conditions of nutrient deficiency such as glucose or glutamine, tumor cells can activate the oncogene c-Myc by regulating the expression of metabolic enzymes such as PHGDH and PSAT1, and support the survival of tumor cells. Other metabolic enzymes that enhance de novo synthesis of serine and maintain redox homeostasis. In addition, under stress conditions of hypoxia or nutrient deficiency, tumor cells produce acetyl-CoA by ingesting minimal two-carbon fatty acids (such as acetoacetate) to provide energy for their own survival and promote themselves through biological macromolecules (such as fatty acids). Survive. Similarly, metabolites generated by the breakdown of ketone bodies by tumor cells can enter the TCA (tricarboxylic acid) cycle to provide ATP for cell survival. Therefore, the metabolic pattern of tumor cells is complex and changeable, and it will choose the best metabolic pattern suitable for its own survival according to different environments.
Immune cell metabolism
The immune system contains a variety of immune cells, such as macrophages, neutrophils, monocytes, eosinophils, basophils, lymphocytes, and natural killer cells. When the body is in a steady state, these cells are in a quiescent state, and when the body is stimulated by infection, inflammation or other external substances, these cells are rapidly activated and respond.
Interestingly, complex metabolic patterns similar to those of tumor cells are also present in immune cells. Recent studies have shown significant differences in the energy expenditure of immune cells between resting and activated states. For example, the metabolism of naive T cells is essentially static, showing zero proliferation, and thus only needs to maintain minimal nutrient intake, minimal glycolytic rate, and minimal biosynthesis. ATP is mainly produced by oxidative phosphorylation (OXPHOS). Once activated into effector T cells (Teffs) by external stimuli, it exhibits a metabolically activated state with increased nutrient uptake, increased rates of glycolysis, and synthetic accumulation of proteins, lipids, and nucleotides. At the same time, mitochondrial oxygen consumption is reduced, and finally T cells gain the ability to grow and proliferate, produce daughter cells, and play a killing role.
In addition, activated neutrophils, M1 macrophages, and iNOS-expressing dendritic cells (DCs) mainly rely on glycolysis for energy. Regulatory T cells (Treg) and M2 macrophages mainly rely on oxidative phosphorylation generated by fatty acid oxidation (FAO) to provide energy. Different metabolic patterns also affect the differentiation of different immune cell subsets.
Nutrient competition between tumor cells and immune cells
Metabolic turnover is not unique to cancer cells, but is also characteristic of other rapidly proliferating cells, such as activated T cells, Treg cells, neutrophils, etc. Glucose is the nutrient that tumor cells absorb and consume the most and is most dependent on, and it is also an important energy substance necessary for the activation, differentiation and function of immune cells.
Studies have found that tumors can inhibit the function of tumor-infiltrating T cells by competitive glucose uptake, even when there are enough tumor antigens for T cells to recognize. Furthermore, the glycolytic activity of tumor cells may limit glucose consumption by TIL cells, leading to T cell exhaustion and immune escape.
Although the competitive uptake of glucose in the tumor microenvironment is responsible for impaired T cell function, the expression of amino acids, glutamine, fatty acids and other metabolites or growth factors and corresponding transporters on the cell surface are also important in affecting immune cell function. factor. Furthermore, high levels of lactate and low pH, hypoxia, and high levels of ROS are equally prevalent in the TME, ultimately leading to tumor progression and immune escape. Therefore, targeting these metabolic pathways in tumors may be a promising strategy to overcome the deleterious effects of metabolic competition between the tumor and the immune system and enhance tumor immunogenicity.
The effect of tumor metabolites on tumor immunity
In addition to nutrient depletion, metabolites produced by tumor cells can have profound effects on immune cells in the microenvironment.
Abnormal glycolysis of tumors means that tumor cells consume a large amount of glucose and produce a large amount of lactate even in the presence of sufficient oxygen, and the corresponding production rate of OXPHOS is low. Lactic acid accumulates in cells and is then exported to the extracellular environment by activating monocarboxylate transporters (MCTs) on the cell membrane, especially monocarboxylate transporter 4 (MCT4), ultimately forming an acidic TME. The low pH of the TME has been shown to favor the selection of more aggressive tumor cells and suppress tumor immunity to promote tumor progression.
In addition, recent clinical studies have found that serum lactate levels increase significantly with increasing tumor burden in patients. Indeed, lactate produced by tumor cells may contribute to tumorigenesis by promoting IL-23 and IL-17-mediated inflammation. In addition to modulating immune responses, lactate produced by tumor-associated fibroblasts (CAFs) can also be used by tumor cells as an alternative nutrient source.
Lactic acid also affects the function of NK cells, thereby impairing the secretion of IFN-γ. Mechanistic studies have shown that excessive intake of pathological concentrations of lactate by NK cells can cause intracellular acidification, inhibit the up-regulation of nuclear factor-activated T cells (NFAT) signaling, reduce NFAT-regulated IFN-γ production, and promote cell apoptosis.
Glutamine metabolism as a whole is a key factor in tumor cell metabolism. Glutamine is important for nucleotide synthesis, amino acid production, redox balance, glycosylation, extracellular matrix production, autophagy, and epigenetics. Studies have shown that glutamine plays an important role in the growth of normal and cancer cells. In the presence of nutrient deficiencies, cancer cells can obtain glutamine by breaking down the macromolecule.
In addition to tumor cells, glutamine is highly utilized by immune cells to support cell fate decisions and immune responses, such as lymphocytes, macrophages, and neutrophils, and lack of glutamine inhibits T cell proliferation and cytokine production. In addition, glutamine metabolism plays an important role in activating immune cells and regulating the transformation of CD4+ T cells into an inflammatory subtype.
Glutamine has a high utilization rate in macrophages and neutrophils, and with the increase in glutamine utilization rate, the apoptosis rate of immune cells decreases significantly. By blocking the glutamine pathway in tumor cells and increasing the amino acid content in the tumor microenvironment, the killing effect of immune cells can be enhanced. This suggests that targeting glutamine metabolism may be a new approach to cancer treatment.
Arachidonic acid is an important class of eicosapentaenoic acid, which is related to essential fatty acids in tumor cells and is an important substrate for the synthesis of prostaglandins. PGE2 is an important cell growth regulator in cells, and it is also a highly active inflammatory mediator in the inflammatory response. It can also participate in the immune response as an immunosuppressive factor. Tumor-associated fibroblast-derived PGE2 or other sources of PGE2 can induce tumor cell invasion and participate in tumor progression by stimulating angiogenesis, cell invasion and metastasis, and inhibit apoptosis to promote cell survival through multiple signaling pathways.
In addition, PGE2 can also affect other cells in the microenvironment through autocrine and paracrine ways, disrupting the immune response. For example, PGE2 suppresses immune responses by inhibiting Th1 differentiation, B cell function, T cell activation, and allergic responses, and in addition, PGE2 can exert anti-inflammatory effects on natural immune cells such as neutrophils, monocytes, and natural killer cells . More importantly, the accumulation of PGE2 secreted by tumor cells can convert tumor suppressor M1 macrophages into cancer-promoting M2 macrophages. PGE2 secreted by tumor cells can also stimulate myeloid cells to secrete tumor-promoting factors CXCL1, IL-6 and granulocyte colony-stimulating factor (G-CSF), and inhibit lipopolysaccharide (LPS)-stimulated myeloid cells to secrete TNF-α and IL- 12. Inhibit the activation of type I interferon-dependent innate immune cells, and inhibit T cells from targeting tumor antigens, so as to achieve the purpose of immune escape and tumorigenesis.
Most tumor cells lack ASS1 (argininosuccinate synthase 1), a key enzyme in the production of arginine, thus resulting in a loss of intracellular arginine synthesis. In this case, tumor cells use exogenous arginine to compensate for the lack of key metabolic enzymes in the cell caused by the lack of arginine. Interestingly, arginine metabolism also plays a crucial role in T cell activation and regulation of immune responses.
In cells, arginine mainly generates urea, L-ornithine and nitric oxide through the reaction of arginase (ARG) and nitric oxide synthase (NOS). Studies report that accumulation of ARG1-expressing immune regulatory cells in the TME, including M2-like tumor-associated macrophages (TAMs), tolerogenic DCs, and Treg cells, may inhibit antitumor immunity by degrading arginine, thereby limiting T cell response to tumors. utilization of this amino acid.
More importantly, some studies have pointed out that arginine absorbed by tumor cells in the tumor microenvironment is mainly provided by myeloid cells (macrophages, monocytes, myeloid suppressor cells, neutrophils, etc.). This means that tumor cells will consume a large amount of arginine in the TME, resulting in a lack of arginine in the TME, so the activation of anti-tumor immune cells must be inhibited. Therefore, arginine supplementation and prevention of arginine degradation in the TME are very attractive strategies to reactivate T cell-mediated and NK cell-mediated immune responses.
Tryptophan is an essential amino acid for protein synthesis and other metabolic activities of life. In fact, tryptophan is degraded mainly by two different dioxygenases: IDO1 (indoleamine-2,3-dioxygenase) and TDO2 (tryptophan-2,3-dioxygenase) Convert tryptophan to kynuric acid. High-level expression of these tryptophan-degrading enzymes in tumor cells promotes tumor progression and is associated with poor prognosis in gastric adenocarcinoma patients.
Since the activation of T cells is extremely sensitive to the concentration of tryptophan in the surrounding environment, tryptophan in the microenvironment is metabolized and utilized by tumor cells in large quantities, resulting in the lack of tryptophan, which will trigger T cell apoptosis. IDO1 inhibitors have been shown to alleviate immunosuppression in the TME and promote tumor-specific T cell activation in preclinical models. The efficacy of IDO1 inhibitors combined with immune checkpoint inhibitors (ICIs) in the treatment of melanoma is under evaluation.
Tumor cells often have increased rates of de novo fatty acid synthesis to divert energy production to anabolic pathways that generate plasma membrane phospholipids and signaling molecules. At the same time, fatty acid synthesis provides membranes and other critical lipid cellular structures for immune cell proliferation and is also required for inflammatory macrophage differentiation and function.
Furthermore, abnormal accumulation of lipid metabolites (eg, short-chain fatty acids, long-chain fatty acids, cholesterol, etc.) in tumor-infiltrating myeloid cells, including MDSCs, DCs, and TAMs, has been shown to reprogram these immune cells through metabolic reprogramming. Tilt towards immunosuppressive and anti-inflammatory phenotypes. Therefore, many scholars believe that the regulatory mechanism of fatty acids on immune cells is not to change the composition of cell membranes or become inflammatory mediators, but that fatty acids directly participate in intracellular signal transmission.
Cholesterol is an important component of the cell membrane surface. Rapidly proliferating cells require more membrane structure and more cholesterol synthesis. High expression of cholesterol in tumor cells can protect tumor cells from immune surveillance and resist drug treatment. High cholesterol caused by tumor cells can promote the expression of T-cell suppressive immune checkpoints, thereby making them lose their anti-tumor effects. More importantly, the researchers found that the cholesterol concentration in tumor cells was much higher than that in immune cells. The higher the cholesterol concentration in immune cells, the higher the expression of PD-1, LAG-3, TIM-3 and other immune checkpoints. Cells are also prone to apoptosis, with lower cytotoxicity and proliferative capacity. In fact, high cholesterol disrupts the lipid metabolism network of T cells, thereby suppressing immune function.
Effects of metabolic enzymes on tumor immunity
Results from clinical studies have shown that aerobic glycolytic activity in human tumors is inversely correlated with host antitumor immune responses and the therapeutic outcome of antitumor immunotherapy. For example, three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinase M2 (PKM2), serve as markers for liver cancer and regulate immunity through multiple mechanisms Escape, such as AMPK, PI3K/Akt, HIF-1α, c-Myc, and noncoding RNAs in hepatocellular carcinoma.
In addition to glycolytic enzymes, cholesterol metabolism and transport enzymes also have important effects on immune cell function, production, and activity. The study found that cholesterol esterase ACAT1 in the T cell metabolic pathway is a good regulatory target. Inhibiting the activity of ACAT1 can greatly improve the anti-tumor function of CD8+ T cells.
In addition, extracellular nucleotidase CD39 and CD73 can significantly upregulate tumor extracellular adenosine content, leading to immune tolerance, which in turn leads to uncontrolled tumor growth.
The impact of metabolic signaling pathways on tumor immunity
mTOR signaling pathway
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that is highly conserved from yeast to mammals and plays an important role in regulating cell growth and metabolism. mTOR has two distinct structures and functions: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 can promote anabolism such as protein and nucleic acid synthesis, and inhibit catabolism such as autophagy. mTORC2 can participate in glutamine metabolism and increase glutamine uptake by activating AGC kinase to regulate its cell surface transporter.
The mTOR signaling pathway of tumor cells promotes tumorigenesis and development by affecting tumor immunity. For example, mTORC1 can promote the expression of PD-L1 and inhibit the infiltration of Treg cells, NK cells and T cells, thereby allowing tumor cells to escape the killing of immune cells. Studies on melanoma have found that tumor cells secrete inhibitory cytokines that reduce the infiltration of T cells into the tumor microenvironment, making tumor cells resistant to immune checkpoint inhibitors after mTORC2-induced AKT activation.
AMPK signaling pathway
AMPK is a key molecule regulating cellular energy homeostasis, and the activation of this kinase is a response to intracellular ATP depletion stress, such as hypoglycemia, hypoxia, ischemia, and heat shock. AMPK negatively regulates ATP-consuming biosynthetic processes, including gluconeogenesis, lipid and protein synthesis. Interestingly, AMPK activation cooperates with immune signaling pathways to regulate cellular immunity and control energy metabolism, thereby affecting the activation of immune cells.
There is compelling evidence that AMPK activation blocks inflammatory responses by inhibiting pro-inflammatory signaling pathways. For example, in macrophages, activation of AMPK promotes the polarization of M1 pro-inflammatory macrophages towards an M2 anti-inflammatory phenotype. Furthermore, AMPK activation modulates anti-inflammatory cytokine signaling in macrophages, for example, enhancing IL-10-induced inhibition of LPS-stimulated cytokine production.
In addition, activation of AMPK plays an important role in the differentiation and function of T lymphocytes by regulating their energy metabolism. These results clearly demonstrate the balance between AMPK signaling in controlling energy metabolism and immune responses.
Adenosine signaling pathway
Accumulated adenosine in the tumor microenvironment inhibits the antitumor function of a variety of immune cells, including cytotoxic T cells and natural killer cells, by binding to the cell surface adenosine 2A receptor (A2AR). The exonucleotidases CD39 and CD73 are cell surface molecules that control the production of adenosine by breaking down ATP into AMP and AMP into adenosine, respectively. Treg cells express CD39 and participate in the immunosuppression of TME through the adenosine-A2AR signaling axis. Targeting CD39 and CD73 to inhibit adenosine production is a very attractive strategy to enhance antitumor immunity.
Clearly, metabolic reprogramming targeting tumors and/or immune cells can synergize with anti-tumor immunity. Understanding and exploiting the metabolic crosstalk in tumor cells and immune cells has the potential to improve the low response rates typically achieved with immunotherapy. Although the combination of various metabolic drugs and immunotherapies has been used in clinical trials, to realize the full therapeutic potential of combination therapies, efforts must be made to better understand the metabolic mechanisms of tumor immune evasion and the metabolic demands of immune cells.
It is worth noting that the metabolic program of tumor cells not only affects the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their function, ultimately leading to changes in tumor immune function. Therefore, metabolic intervention can not only improve immune cell responses to tumors, but also increase tumor immunogenicity, thereby expanding the range of cancers that can be effectively treated with immunotherapy.
Source: The cancer metabolic reprogramming and immune response. Mol cancer. 2021 Feb 5.20 : 28.