Will 2DG Make Cancer Immunotherapy More Effective?

Summary 

Different therapeutic modalities are used for the treatment of cancer patients. One of the important cures is the use of immunotherapy. In this therapy, different drugs, vaccines, or antibodies are given to the patient that will boost the immune system of a patient to act strongly against the tumors. But this therapy has many drawbacks that will be discussed in detail later. The most important is the development of resistance against T-Cells by tumors. This can be overcome by using 2DG along with immunotherapeutic drugs. 2DG has such a mechanism of action that it makes the cancer cells low in energy. So, the cells are unable to develop resistance against immunotherapy. 

Introduction 

Cancer cells differ from the normal cells of the body in many different ways, one of the most important differences being in the rate of sugar metabolism. Malignant cells have a far higher glucose metabolic rate as compared to those of normal cells. Because they need more energy for the production of their subclones and their growth, they have increased the production of ATP and pyruvate through glycolysis. They produce energy by glycolysis even if there is plenty of oxygen in the cell as described by Warburg (Annibaldi & Widmann, 2010). 

Many therapeutic strategies are being used to cure cancer patients but all of them have some side effects. Either they are harming the normal body cells or cancer cells repair the damage caused to them by these therapies (Shay & Wright, 2006).

Immunotherapy is a biological therapy that involves white blood cells of the body to fight against cancer. It not only fights against but also destroys the abnormal or cancerous cells in the body (Schuster et al., 2006).

The immune system acts against tumors

The immune system is normally fighting against all types of cancers. Tumor-infiltrating lymphocytes or TILs are usually present around the cancer cells. If these immune cells are found around any tumor, it is an indication that the immune system of that patient is fighting against the disease. 

If we compare the patients, one having TILs around his tumor, and the other one who doesn’t have TILs around his tumor in the body, then it is found that the 1st person with TILs will be performing better than the latter one. 

Need for Immunotherapy 

But cancer cells have different ways to protect themselves from the immune system of the body. Usually, the genetic variations present in the cancer cells do not allow the immune system to fight against them. Moreover, cancer cells have different proteins on their surface, that make them invisible to the immune system components. So, in order to overcome these problems, when the immune system of the patient could not fight against the disorder, and no TILs are found around the tumors, we have to move towards Immunotherapy for treatment (Schuster et al., 2006). 

Chimeric Antigen Receptor (CAR) T cell Therapy

It is also a type of immune therapy in which the T-cells of the patient are replaced in the laboratory. The T-cells from the tumor are removed, and the functional T-cells are inserted into the patient body. This therapy has passed early clinical trials and is now introduced in humans to cure different types of cancers. It has fewer side effects and is more effective and safer. 

The CAR T-cells that are inserted in the patient have co-stimulatory signaling domains that make them function more effectively. Although this therapy is not used widely yet, it can be a promising therapy for the cure of all cancer types. 

Food and Drug Administration (FDA) has approved almost six CAR T-cell therapies from 2017 onwards. They were mostly for the treatment of Blood Cancer (leukemia) patients. 

Limitations of CAR T-cell Therapy and their solution 

CAR T-cell therapy is the fourth most common therapy for cancer worldwide. Although it is a new, effective, and quickly evolving modality, but it has some side effects. The most important drawback of this therapy is the high recurrence rate and low efficacy in solid tumors. To overcome this drawback of the therapy, we can use 2DG while preparing the CAR T-cells. 2DG will change the sugar metabolism in T-cells. This will change the differentiation process of T-cells improving their anti-tumor activity. 

N-linked glycosylation

The attachment of a carbohydrate that consists of several sugar molecules, called oligosaccharides, to the N-terminal of a protein, is called N-linked glycosylation. This occurs in the endoplasmic reticulum. The consensus sequence for N-linked glycosylation is Asn-N-Ser/Thr. Here N can be any standard amino acid other than proline. This process occurs in almost all eukaryotic organisms and is mandatory for the survival of organisms. 

Process of N-linked Glycosylation 

The addition of oligosaccharides to the N-terminal of protein involves many enzymes like glycosidases and glycosyltransferases. These enzymes are transmembrane proteins functioning in the ER. Oligosaccharides are added to the Asparagine residues on proteins and affect their structure and function (Kukuruzinska & Lennon, 1998). 

Blockage of N-glycosylation in cancer cells

Cancer cells have hyperactivation of the glycolytic processes. They need large amounts of energy for their survival which is produced either by glycolysis or by oxidative phosphorylation. They are usually resistant to the immune system response as they activate different biochemical pathways that protect them and make them resistant. 

Different experiments have been performed on cancer cells by using glucose antimetabolite 2DG that inhibits the glycolytic process. It is also found that 2DG not only phosphorylates glucose but also regulates the N-linked glycosylation of different proteins in the cells(Sasawatari et al., 2020). 

2-DG is converted into 2-deoxy-D-mannose that is incorporated into the oligosaccharide chains and inhibits the biosynthesis of glycosylated proteins that are usually termed N-glycans after the addition of oligosaccharides to their N-terminal. When these proteins are not glycosylated, this affects their properties and function of these proteins. Usually, the cell cycle checkpoint proteins are inhibited in this way. That will block the cell cycle and hence the proliferation of cells (Kim et al., 2020).

Types of Immunotherapies

In order to cure different tumors, we have found different types of immunotherapies that help the body of the patient fight against cancer. Some of these types are discussed below.

Monoclonal antibodiesAntibodies are proteins that bind the foreign materials present within the body and kill them so they may not harm the organism. Usually, antibodies are produced within the body by T-cells. But in the case of cancer patients, when the immune system is not responding to the disease. We use antibodies that are prepared in the laboratory and given to the patient as immunotherapy. They will bind the proteins on tumors that are making tumors invisible to the immune system. When these target proteins become nonfunctional, tumors become visible to the immune system and start their action against cancer (Samstein et al., 2019). 

1. Vaccines

These are the treatment vaccines that are given to cancer patients. These vaccines activate the immune system in the patient’s body so that it starts its action against the tumor cells (Samstein et al., 2019).

2. Modulators of the immune system

These are specific proteins targeting the specific parts of the immune system of the patient and activating them. When the immune system is activated, it will start destroying the tumor cells (Samstein et al., 2019).

3. Immune system checkpoint inhibitors

Immune system checkpoints do not allow the system to act strongly against foreign antigens. Immune system checkpoint inhibitors are some specific drugs that are given to cancer patients. These drugs will inhibit the checkpoints and the immune system, and its components will be able to act more strongly against the tumors.

4. T-cell transfer therapy

It is a type of immunotherapy, in which T cells from the tumor area of the body of the patient are removed in the laboratory, and are replaced by some more effective cells, then injected back into the body by using a needle in a vein. These new T cells thus injected into the body will help in fighting against the tumor in a more effective way (Samstein et al., 2019).

Limitations of Cancer Immunotherapy 

Although different types of immunotherapies are used for the treatment of cancer patients. But it has many side effects. The most important drawback of using this therapy is that the cancer cells develop resistance after some time. As the malignant cells have a large amount of energy being produced by glycolysis, they downregulate the signaling pathways that are important for the regulation of T-Cells. When T-cells don’t mature properly, they can not perform their function in the tumor cells. And hence, the cells overcome the response of the immune system that was elevated by immunotherapy.

How do we overcome these Limitations?

In order to overcome the limitations of immunotherapy for cancer, we should target the energy-producing mechanism in the tumor cells after providing immunotherapy. When there is limited energy in the cell, it will not be able to downregulate the signaling pathways affecting the regulation and maturation of T-Cells. 

 

Combination Experimental findings

To make immunotherapy more effective in cancer cells, we can use immunotherapy and glucose antimetabolite 2DG together.

Triple Negative Breast Cancer (TNBC) has increased programmed death-ligand 1 (PD-L1) expression, and its immunosuppressive nature makes it suitable for immune checkpoint blockade therapy. However, the response rate of TNBC to anti-PD-L1 or anti-programmed cell death protein 1 (PD-1) therapy remains unsatisfactory, as only 10-20% of TNBC patients have a partial response. Glycosylated PD-L1, the functional form of PD-L1, is required for PD-L1-PD-1 interaction. TNBC cells have significantly higher levels of glycosylated PD-L1 than non-TNBC cells do. In a screening of glucose analogs to block PD-L1 glycosylation, we found that 2-deoxyglucose (2-DG) can act as a glucose analog to decrease PD-L1 glycosylation because the glycosylation plays an important role in the PD-L1 protein’s stability and immunosuppressive function (Bareun Kim et al. Mol Carcinog. 2020 Jul.)

Mechanisms of action of 2DG

 

1. Low Sugar Metabolism

By using 2DG, the cancer cells are unable to take up glucose from their environment. And hence no ATP will be produced. Because of this energy deprivation, cells will not be able to overcome the response of the immune system. And they will not repair the damage caused by the immunotherapy process (Kurtoglu et al., 2007).

2. Inhibition of Glycolytic Pathway

2DG can bind to the glucose transporter proteins in the cell, but it cannot be metabolized like normal glucose. So, it will inhibit the glycolytic pathway in the cells, thus, no ATP production will take place.

3. Change in Gene Expression Regulation

2DG also targets Chaperone proteins which are very important for the proper folding of proteins. Proteins can only function well when they are folded properly. So, the misfolded proteins after 2DG administration in the cells, will not act as transcription factors to activate the expression of genes. In this way, genes that are important for the growth of cancer cells will not be activated and the growth of cells get inhibited.

4. Apoptosis

Apoptosis is the process by which a cell willingly self-destructs. When 2DG is given to cancer patients, it activates different proteins that are required for the activation of an apoptotic pathway like Caspase 3 and PARP. So, the cancer cells die (Kurtoglu et al., 2007).

 5. Blocking N-linked Glycosylation

2DG modified N-glycosylation, which augmented antitumor activity and cell surface retention of IL-2R of T cells. Moreover, 2DG treatment prevented T cells from binding to galectin-3, a potent tumor Ag associated with T cell anergy. Our results, therefore, suggest that modifying N-glycosylation of T cells with 2DG could improve the efficacy of T cell-based immunotherapies against cancer.

 

Conclusion 

Many therapeutic modalities are being used for the treatment of cancer patients. One of the standard treatments against cancer is immunotherapy. In this therapy, drugs are given to the patient that activates or elicits the immune system of the patient. Then the immune system works against the tumors more efficiently.

But the drawback of this therapy is that the cancer cells develop resistance by downregulating the biochemical pathways that are important for the immune system to function. This limitation of immunotherapy can be overcome by using combinational therapy. immunotherapy is used in combination with 2DG, a glucose analog, that will make it more effective for cancer treatment

2DG will make the tumor cells deprived of energy, so they will not be able to downregulate the pathways vital for the immune system to show a response against tumors. So, 2DG can make immunotherapy more effective.

 

References 

Annibaldi, A., & Widmann, C. (2010). Glucose metabolism in cancer cells. Current Opinion in Nutrition and Metabolic Care13(4), 466–470. https://doi.org/10.1097/MCO.0b013e32833a5577

Klevorn, L. E., & Teague, R. M. (2016). Adapting Cancer Immunotherapy-Models for the Real World. Trends in Immunology37(6), 354–363. https://doi.org/10.1016/j.it.2016.03.010

Kurtoglu, M., Maher, J. C., & Lampidis, T. J. (2007). Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells. Antioxidants and Redox Signaling9(9), 1383–1390. https://doi.org/10.1089/ars.2007.1714

Samstein, R. M., Lee, C. H., Shoushtari, A. N., Hellmann, M. D., Shen, R., Janjigian, Y. Y., Barron, D. A., Zehir, A., Jordan, E. J., Omuro, A., Kaley, T. J., Kendall, S. M., Motzer, R. J., Hakimi, A. A., Voss, M. H., Russo, P., Rosenberg, J., Iyer, G., Bochner, B. H., … Morris, L. G. T. (2019). Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genetics51(2), 202–206. https://doi.org/10.1038/s41588-018-0312-8

Schuster, M., Nechansky, A., Loibner, H., & Kircheis, R. (2006). Cancer immunotherapy. Biotechnology Journal1(2), 138–147. https://doi.org/10.1002/biot.200500044

Shay, J. W., & Wright, W. E. (2006). Telomerase therapeutics for cancer: Challenges and new directions. Nature Reviews Drug Discovery5(7), 577–584. https://doi.org/10.1038/nrd2081

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