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Metabolism involves a series of biochemical reactions that convert nutrients into metabolites that play an important role in maintaining cellular homeostasis and in response to intracellular and extracellular stimuli. Metabolic changes are one of the important features of tumors. In order to maintain sustained proliferation, tumor cells must adjust their metabolic and nutrient acquisition.

A growing body of research has found that metabolic changes in the tumor microenvironment (TME) can suppress immune immunity such as immune cell infiltration by producing immunosuppressive metabolites. The metabolic disorder of cancer cells further affects the expression of cell surface markers, thereby interfering with immune monitoring. Metabolic pathways that have been found to be associated with immunotherapeutic resistance include PI3K-Akt-mTOR, hypoxia-inducible factor (HIF), adenosine, JAK/STAT, and Wnt/β-catenin.

On March 26, in a review of Nature Reviews Clinical Oncology entitled “Navigating metabolic pathways to enhance antitumour immunity and immunotherapy,” scientists from Switzerland, the United States, and Belgium summarized the metabolic pathways associated with tumor immune escape. Weaknesses in these metabolic pathways are discussed and these weaknesses may be used to enhance cancer immunotherapy.

 

Glycolysis

 

The Warburg effect is a classic example of changes in tumor metabolism. It is characterized by the fact that even in the presence of sufficient oxygen, tumor cells can use large amounts of glucose and produce lactic acid by glycolysis (normal cells, glycolysis in anaerobic or hypoxic At the same time, correspondingly, the rate of oxidative phosphorylation (OXPHOS) is low.

 

Lactic acid is delivered to the external environment of cancer cells by a monocarboxylic acid transporter (especially MCT4), resulting in an acidic TME. Over the past decade, aerobic glycolysis and the resulting acidic TME have been shown to have a major impact on T cell-mediated anti-tumor immune responses and tumor-infiltrating myeloid activity (figure 1). For example, two of the Cell published in 2015 confirmed that mTOR activity, activation of T cell nuclear factor (NFAT) signaling, and glycolytic activity of tumor-infiltrating lymphocytes (TILs) were reduced by the higher glucose consumption rate of tumor cells. This leads to impaired production of anti-tumor effect molecules.

Figure 1 Metabolic stress in tumor microenvironment and its effect on anti-tumor immunity

 

 

Amino acids and their derivatives

 

Glutamine and glutamic acid

 

In addition to high glucose consumption, some tumors are consumed by high glutamine to meet the metabolic needs of cancer cells. Increased glutamine anaplerosis in tumor cells leads to increased ammonia release; exposure to ammonia activates autophagy in adjacent cells, such as cancer-associated fibroblasts (CAFs). In turn, ammonia-activated autophagy in CAFs can further support the growth of tumor cells by promoting the release of glutamine from CAFs. In addition, products of glutamine metabolism (such as glutamate, aspartic acid) can also regulate tumor cell metabolism, epigenetics, nucleotide synthesis and redox balance.

 

It is worth mentioning that lactic acid also promotes the expression of glutamine transporters ASCT2 and glutaminase 1 (GLS) in tumor cells (Fig. 1).

 

Several compounds that target glutamine replenishment are now being developed for anti-cancer therapy. Some of these drugs have been shown to have anticancer effects, such as the GLS allosteric inhibitor CB-839. CB-839 has been shown to be effective in inhibiting glutamine decomposition and has good activity in preclinical models of triple negative breast cancer and hematological malignancies. Currently, a number of clinical trials are evaluating CB-839. These clinical trials involve patients with solid tumors or hematologic malignancies, both single-agent and immunological checkpoint inhibitors (ICIs).

 

Arginine

 

Arginine metabolism also plays an important role in T cell activation and regulation of immune responses. Accumulation of immunoregulatory cells (including M2-like tumor-associated macrophages, Treg cells, etc.) expressing arginase 1 (ARG1) in TME inhibits resistance by degrading arginine (restricting the availability of arginine by T cells) Tumor immunity.

 

Studies have shown that by arginine-stimulated cytotoxicity of T cells and NK cells and production of effector cytokines, treatment with PD-L1 antibody significantly enhances the anti-tumor immune response and prolongs the survival of osteosarcoma mice. Therefore, supplementation of arginine and prevention of arginine degradation in TME is an attractive strategy to reactivate T cell and NK cell mediated immune responses. This method is being tested in clinical trials, such as the ARG1 inhibitor INCB001158 being used in conjunction with the PD-1 antibody Keytruda.

 

Tryptophan

 

Studies have shown that high levels of expression of tryptophan degrading enzymes in tumor cells promote tumor progression and are associated with poor prognosis in patients with gastric cancer. High levels of IDO and TDO in tumors are thought to reduce the availability of tryptophan in TME, which in turn inhibits the tumoricidal function of T cells. In addition to depriving T cells of tryptophan, IDO and TDO also break down tryptophan into kynurenine, which accumulates to reduce the proliferation of effector T cells (Fig. 1). The first IDO1 inhibitor (1-methyltryptophan) has been shown to attenuate TME immunosuppression and promote tumor-specific T cell activation in preclinical models. Following this discovery, the IDO inhibitor indoximod, the IDO1 inhibitor navoximod, and the IDO1–TDO dual inhibitors HTI-1090 (SHR9146) and DN1406131 have entered clinical testing. Among them, indoximod is being developed to treat melanoma patients in combination with CTLA-4 antibody or PD-1 antibody.

 

Adenosine signal

 

The concentration of adenosine in TME was significantly increased. The nucleotide metabolic enzymes CD39 and CD73 play a key role in controlling the production of adenosine. Increased expression of CD39 and CD73 in tumors is associated with poor prognosis in patients with gastrointestinal, gynaecological, and non-small cell lung cancer. In addition to tumor cells, Treg cells can also express CD39 and promote immunosuppression in TME (A2AR, adenosine A2A receptor) via the adenosine-A2AR signal axis.

 

Targeting CD39 and CD73 activities to inhibit adenosine production is also an attractive strategy to enhance anti-tumor immunity. A large number of preclinical studies have shown that treatment with anti-CD73 antibodies can improve the efficacy of ICIs treatment. Similarly, a combination of A2AR antagonists and ICIs can also induce a synergistic anti-tumor response in a mouse model. Some drugs that target the adenosine signaling pathway (such as the A2AR inhibitor CPI-144) are being tested for anticancer efficacy in combination with ICIs.

 

Cyclooxygenase and PGE2 pathway

 

Cyclooxygenase 2 (COX2) is overexpressed in many cancers and is closely related to immunosuppression in TME and high levels of PGE2 production. Numerous studies have shown that inhibition of PGE2 production and its signaling cascade can improve multiple aspects of anti-tumor immune responses. For example, the selective COX2 inhibitor celecoxib induces a synergistic anti-tumor immune response when used in combination with a PD-1 antibody. Clinical trials of some of the same combination therapies have been initiated (Table 1). At the same time, researchers are also developing PGE2 receptor inhibitors. Among them, the selective PGE2 receptor 4 (EP4) antagonist grapiprant is being evaluated as a single agent or in combination with Keytruda for the treatment of non-small cell lung adenocarcinoma or microsatellite stable colorectal cancer patients.

 

Fatty acids and cholesterol

 

Tumor cells typically increase the rate of de novo synthesis of fatty acids to produce cell membrane phospholipids and signaling molecules. A large body of evidence indicates that lipid metabolism of tumor cells and immune cells in TME plays an important role in coordinating immunosuppression. Targeting these metabolic pathways is one way to enhance anti-tumor immunity. In this regard, Chinese scientists have published an important achievement in Nature, demonstrating that the use of cholesterol esterase ACAT1 inhibitor avasimibe to disrupt cholesterol esterification can improve the function and proliferation of effector T cells. Avasimibe synergizes with PD-1 inhibitors to eradicate melanoma in a mouse model. In addition, studies have shown that the lipid species present in TME may regulate the infiltration pattern of effector CD4+ T cells and determine the outcome of targeting lipid metabolism to treat cancer.

 

Metabolic regulation of immune checkpoints

 

In recent years, ICIs have made significant progress in cancer treatment. Such anticancer drugs were originally developed to enhance T cell activation signaling pathways, however, there is increasing evidence that ICIs also affect T cell metabolic fitness (Figure 2). Some studies have found that ICIs affect metabolic communication and competition between tumors and T cells in the tumor microenvironment (TME). For example, the interaction of PD-1 with PD-L1 or PD-L2 can impair metabolic reprogramming of T cells by inhibiting the PI3K-AKT-mTOR pathway.

Figure 2 Regulation of metabolic pathways by immunological checkpoint receptors and ligands

In addition to regulating the metabolism of TILs, immune checkpoints can directly affect the metabolism of tumor cells. Expression of PD-L1 and B7-H3 (also known as CD276) in tumor cells has been shown to stimulate aerobic glycolysis by activating the PI3K-AKT-mTOR pathway.

 

Therefore, inhibition of the PD-1/PD-L1 axis may result in synergistic anticancer effects by promoting reactivation of TILs and metabolic fitness, as well as inhibition of aerobic glycolysis of tumor cells. A preclinical study showed that PD-1/PD-L1 inhibition did enhance the glycolytic activity of T cells.

 

In addition to PD-1, other inhibitory immune checkpoint receptors have also been reported to affect T cell metabolic programs such as CTLA-4, TIM3, and LAG3. For example, TIM3, which is highly expressed on functionally depleted T cells, has been shown to alter T cell metabolism by disrupting the PI3K-AKT-mTOR signal. In addition, basal respiration and aerobic glycolysis rates of LAG3-deficient CD4+ T cells were significantly increased compared to wild-type CD4+ T cells, indicating that LAG3 expression reduces T cell metabolic fitness.

 

Unlike metabolic damage caused by inhibitory immune checkpoint receptors, activating co-stimulatory molecules support T cell activation by stimulating signaling pathways that control transcriptional reprogramming and metabolic switching. For example, the CD28 signal enhances the metabolic fitness of T cells by simultaneously activating aerobic glycolysis and promoting mitochondrial fusion (Figure 2). The 4-1BB signal, which significantly enhances CD8+ T cell proliferation, activates glucose and fatty acid metabolism. In addition, double co-stimulation of 4-1BB and OX40 enhanced glycolysis of CD8+ T cells. Activation of GITR upregulates nutrient uptake, lipid storage, glycolysis, and oxygen consumption of CD8+ T cells.

 

In summary, these published papers show that ICIs and costimulatory receptor agonists have important effects on T cell metabolism. Because TME exerts various metabolic stresses on TILs, combining ICIs and/or costimulatory receptor agonists with metabolic therapy (such as LDHA inhibitors, MCT1 and/or MCT4 inhibitors or PFKFB3 inhibitors) may improve The efficacy of immunotherapy.

 

Metabolic intervention for adoptive T cell transfer immunotherapy

 

TILs

 

Metabolic regulation plays a key role in T cells activated during the primary immune response. This finding was originally derived from a Nature related to mTORC1 published in 2009. Later studies have found that inhibition of mTORC2-AKT signaling or glycolysis during CD8+ T cell expansion can confer a T cell memory phenotype and enhance antitumor activity. These findings suggest that, in clinical settings, metabolic interventions may be considered for use in combination with adoptive T cell transfer (ACT) immunotherapy. In addition, a better understanding of the process of inducing metabolic T cell failure in TME may also reveal new therapeutic targets.

 

For example, a Cell published in 2015 confirmed that glucose deficiency in TME may result in insufficient phosphoenolpyruvate (PEP) in TILs. The increase in PEP production of melanoma antigen-specific T cells by overexpression of PCK1 inhibits the activity of SERCA, resulting in sustained effector function of ACT immunotherapy (SERCA: sarcoplasmic/endoplasmic reticulum calcium ATPase 3).

 

A Nature published in 2016 found that cells in tumors release potassium ions into the extracellular space near death. Potassium levels in TILs are also higher, which inhibits TCR-driven AKT–mTOR signaling as well as anti-tumor activity. Increased potassium efflux by overexpression of potassium channel Kv1.3 in tumor antigen-specific CD8+ T cells during in vitro expansion can improve outcomes in ACT-treated melanoma mice: enhanced tumor clearance and improved survival .

 

Currently, a clinical trial investigating the combination of TIL-based ACT immunotherapy with T-cell metabolic intervention is ongoing (NCT02489266).

Figure 3 Enhances the metabolic pathway of adoptive T cell therapy

CAR-T therapy

 

Another representative of ACT immunotherapy is CAR-T therapy. Currently, the US FDA has approved two CAR-T products targeting CD19 (Kymriah and Yescarta) for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma. A study published in 2017 showed that inhibition of AKT during CD19-CAR-T expansion can alter the metabolism of CAR-T cells, promote their differentiation into memory phenotype, and improve the efficacy of treatment of B-ALL. In addition, studies have shown that inhibition of mTOR or glycolytic pathway favors T cell differentiation into naïve and memory phenotype; however, this inhibition also leads to a significant decrease in cell proliferation.

 

In addition to the above methods, the costimulatory domains used in the CAR structure have also been shown to determine the metabolic fitness and persistence of CAR-T cell products. For example, using CD28 co-stimulation of glycolysis and effector domains can CAR-T cell differentiation; the use of 4-1BB costimulatory domain may induce mitochondrial biogenesis (mitochondrial biogenesis), OXPHOS memory T cells and the subsequent differentiation, This results in better in vivo persistence of CAR-T therapy.

 

In summary, the evidence is constantly revealed that immune metabolism is a key factor in determining the outcome of CAR-T cell therapy and other ACT immunotherapy. It is very important that these cell therapies, because they contain in vitro engineering and amplification processes, are well suited to manipulate the key metabolic mechanisms of T cells (Figure 3).

 

Summary

 

In the past decade, the development of immunotherapy has led to a shift in the cancer treatment paradigm. However, in fact, most patients do not benefit from immunotherapy, which may be due to insufficient reprogramming of immunosuppressive TME, which limits the recovery of anti-tumor immunity.

 

In summary, the review states:

 

1) TME will exert metabolic pressure on infiltrating immune cells, resulting in local immunosuppression and tumor immune escape.

 

2) Interventions targeting abnormal metabolic characteristics of tumor cells may reprogram the immune status of TME;

 

3) The immune checkpoint regulates the activation and function of T cells in part by affecting metabolic reprogramming and mitochondrial adaptation of these cells;

4) Drugs targeting metabolic pathways active in TME may synergize with immunological checkpoint inhibitors by mitigating the metabolic stress of TILs;

5) Regulating the metabolic process of T cells during TIL expansion or CAR-T cell production is a promising strategy to improve the efficacy of adoptive T cell immunotherapy.

However, although various combinations of metabolic drugs and immunotherapies have been tested in clinical trials (Table 1), scientists in the future still need to better understand the metabolic mechanisms of tumor immune evasion and the metabolic requirements of anti-tumor immune cells. It is important to fully exploit effective combination therapies.

 

Finally, it is worth mentioning that metabolic procedures also affect antigen presentation and recognition. Therefore, metabolic interventions may also increase the immunogenicity of cancer cells, thereby broadening the range of cancers that can be effectively treated by immunotherapy.

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