Selenium compounds boost immune system to fight against cancer

 

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Cancer types such as melanoma, prostate cancer and certain types of leukemia weaken the body by over-activating the natural immune system. Researchers from the University of Copenhagen have now demonstrated that selenium -- naturally found in, e.g., garlic and broccoli -- slows down the immune over-response. In the long term, this may improve cancer treatment. The findings have been published in the Journal of Biological Chemistry.

The immune system is designed to remove things not normally found in the body. Cells undergoing change, e.g. precursors of cancer cells, are therefore normally recognised and removed by the immune system. Unfortunately, the different cancer cells contain mechanisms that block the immune system's ability to recognise them, allowing them to freely continue cancer development.

Certain cancer cells overexpress immunostimulatory molecules in liquid form. Such over-stimulation has a negative impact on the immune system:

"You can say that the stimulating molecules over-activate the immune system and cause it to collapse, and we are, of course, interested in blocking this mechanism. We have now shown that certain selenium compounds, which are naturally found in, e.g., garlic and broccoli, effectively block the special immunostimulatory molecule that plays a serious role for aggressive cancers such as melanoma, prostate cancer and certain types of leukemia," says Professor Søren Skov, Department of Veterinary Disease Biology, University of Copenhagen.

Dissolved molecules

In this study, the researchers are focusing on the so-called NGK2D ligands. There are eight variants, of which one in particular has caught the researchers' attention, because it assumes liquid form. It is precisely the molecular dissolution that causes serious problems, once the cancer is raging. The entire bloodstream is, so to speak, infected, and the molecule is therefore used as a marker of serious illness:

"Molecules are found both on the surface of the cancer cells and dissolved in the blood of the affected person. We are now able to show that selenium compounds appear to have a very beneficial effect when it comes to neutralising the special variant of the NGK2D ligand -- both in soluble form and when the molecule is placed on the cell surface," says Professor Søren Skov.

Better drugs in future

The researchers are constantly learning more about the disease mechanisms causing aggressive cancers in the skin, blood and reproductive organs:

"The overexpression seen in cancers such as melanoma, prostate cancer and certain types of leukemia significantly impairs the immune system. If we can find ways to slow down the over-stimulation, we are on the right track. The new results are yet another small step towards better cancer drugs with fewer adverse effects," says Søren Skov.

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Story Source:

The above story is based on materials provided by University of Copenhagen - The Faculty of Health and Medical Sciences. Note: Materials may be edited for content and length.

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Journal Reference:

1. M. Hagemann-Jensen, F. Uhlenbrock, S. Kehlet, L. Andresen, C. Gabel-Jensen, L. Ellgaard, B. Gammelgaard, S. Skov. The Selenium Metabolite Methylselenol Regulates the Expression of Ligands That Trigger Immune Activation through the Lymphocyte Receptor NKG2D. Journal of Biological Chemistry, 2014; 289 (45): 31576 DOI: 10.1074/jbc.M114.591537

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'Cyberwar' against cancer gets a boost from intelligent nanocarriers

 

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Two years ago, Prof. Eshel Ben-Jacob of Tel Aviv University's School of Physics and Astronomy and Rice University's Center for Theoretical Biological Physics made the startling discovery that cancer, like an enemy hacker in cyberspace, targets the body's communication network to inflict widespread damage on the entire system. Cancer, he found, possessed special traits for cooperative behavior and used intricate communication to distribute tasks, share resources, and make decisions.

In research published in the Early Edition of the Proceedings of the National Academy of Sciences, Prof. Ben-Jacob and researchers from Rice University and the University of Texas M.D. Anderson Cancer Center, the leading cancer treatment center in the U.S., offer new insight into the lethal interaction between cancer cells and the immune system's communications network. Prof. Ben-Jacob and the study co-authors developed a computer program that models a specific channel of cell-to-cell communication involving exosomes (nanocarriers with crucial cellular "intelligence") that both cancer and immune cells harness to communicate with other cells.

"Recent research has found that cancer is already adept at using a kind of 'cyberwarfare' against the immune system. We studied the interplay between cancer and the immune system to see how we might be able to shift the balance against cancer," said Prof. Ben-Jacob, noting a difference between the innate and the adaptive qualities of the immune system. "In the beginning, cancer is inhibited by the body's innate immunity. But once cancer escapes the immunity, there is a race between the progression of cancer and the ability of the adaptive immune system to recognize and act against it."

Cyberwarfare of the body

"What we are dealing with is cyberwarfare, pure and simple. Cancer uses the immune systems' own communications network to attack not the soldiers but the generals that are coordinating the body's defense," said Prof. Ben-Jacob.

To better understand the role of exosome-mediated cell-to-cell communication in the battle between cancer and the immune system, the researchers created a computer model that captured the exosomal exchange between cancer cells, dendritic cells, and the other cells in the immune system.

The new model is based on earlier research, which showed that dendritic cells, mediators between the body's innate and adaptive immune systems (the former protects against all threats at all times and the latter guards more efficiently against specific, established dangers), employed exosomes to fulfil their task. The researchers discovered that, overtaken by cancer, these nanocarriers, which contain such vital components as signaling proteins, RNA snippets, and microRNAs, can command cells to change their tasks, placing the entire system at risk.

Finding a better balance between the strong and the weak

According to the new research, three possible cancer states can exist: strong, intermediary, and weak. The intermediary state -- in which cancer is neither strong nor weak and in which the immune system is on high alert -- could be the key to a new therapeutic approach with reduced side effects. Prof. Ben-Jacob believes it is possible to force cancer from a strong to moderate state, and then from a moderate to weak state, by alternating cycles of radiation or chemotherapy with immune-boosting treatments.

"Our first important discovery is that this situation is due to the exosome-based cyberwar between cancer and the immune system," said Prof. Ben-Jacob. "Without exosomes, the two possible states are only strong-weak and weak-strong. With exosomes, an intermediary state opens a new way to treat cancer using very a different approach."

Prof. Ben-Jacob likened the exchange to a tug-of-war between cancer and the immune system. "The challenge is to be familiar with the battlefield so that we can manipulate cancer therapies to change the balance in favor of the immune system. When cancer is detected, it is almost always in the context of a cancer-immunity competition," said Prof. Ben-Jacob. "We showed that the way to stop and reverse tumor progression without causing strong side effects is an individualized approach of mixed treatments -- i.e., four days of radiation followed by a few days of immune system boosting, followed again by four days of radiation, and so on. If provided in the right order, the treatments could indeed shift the balance toward the immune system's 'victory' in reducing the cancer to the moderate-strong state."

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Story Source:

The above story is based on materials provided by American Friends of Tel Aviv University. Note: Materials may be edited for content and length.

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Journal Reference:

1. B. A. Camley, Y. Zhang, Y. Zhao, B. Li, E. Ben-Jacob, H. Levine, W.-J. Rappel. Polarity mechanisms such as contact inhibition of locomotion regulate persistent rotational motion of mammalian cells on micropatterns. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1414498111

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Failed cancer vaccines might live again with new immune drugs

Health

 

Reuters September 28, 2014 , 2 : 04 pm GST

 

Using vaccines to fight cancer is a field littered with failures but experts believe it is possible the approach could get a new lease of life if such shots are combined with a new class of drugs called checkpoint inhibitors.
Unlike traditional preventative vaccines, therapeutic cancer vaccines are designed for people with established disease and are supposed to boost the patient's immune system to keep tumours at bay.
Unfortunately, the theory has not worked out in practice because, while the vaccines are successful at triggering a response from the "foot soldiers" of the immune system, cancer cells still manage to escape detection.
The result has been a series of failures with high-profile experimental cancer vaccines such as Merck KGaA's Stimuvax and GlaxoSmithKline's MAGE-A3.

GSK threw in the towel on its vaccine in April, dashing hopes for a project that was once seen as a potential multibillion-dollar sales opportunity in lung cancer and melanoma.
Johan Vansteenkiste of Belgium's University Hospitals Leuven, who led research into use of MAGE-A3 in lung cancer, reported full results of the failure at a medical meeting on Sunday and said the setback was a clear disappointment.
But he thinks the new checkpoint inhibitors, which are designed to stop the molecular trickery that is used by tumour cells to escape detection by the immune system, could finally unlock the value of such vaccines.
"For future progress, I think a combination of vaccination and checkpoint inhibition may be of major interest," he told the European Society of Medical Oncology annual congress in Madrid.
Advances with checkpoint inhibitors - particularly so-called PD-1 and PD-L1 drugs being developed by Bristol-Myers Squibb , Merck & Co, Roche and AstraZeneca - is dominating discussion at this year's ESMO meeting.
The new drugs are generating promising results in a growing range of tumour types and scientists are now casting around for novel ways to combine them with other therapies to get even better outcomes.
Therapeutic vaccines could be one such promising avenue, since they have very few side effects compared to many harsh cancer treatments.
Roche Chief Executive Severin Schwan said earlier this month that the Swiss drugmaker - the world's largest maker of cancer drugs - was already exploring ways of combining its checkpoint inhibitors with vaccines that had failed in tests when given on their own.

Cancer immunotherapy: Potential new target found

 

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Scientists have found a way to target elusive cells that suppress immune response, depleting them with peptides that spare other important cells and shrink tumors in preclinical experiments, according to a paper published online by Nature Medicine.

"We've known about these cells blocking immune response for a decade, but haven't been able to shut them down for lack of an identified target," said the paper's senior author, Larry Kwak, M.D., Ph.D., chair of Lymphoma/Myeloma and director of the Center for Cancer Immunology Research at The University of Texas MD Anderson Cancer Center.

The cells, called myeloid-derived suppressor cells (MDSCs), are found abundantly in the microenvironment around tumors. Created with other blood cells in the bone marrow, they interfere with activation and proliferation of T cells, the immune system's attack cells. MDSCs have been shown in mouse models to accelerate cancer progression and metastasis.

"This is the first demonstration of a molecule on these cells that allows us to make an antibody, in this case a peptide, to bind to them and get rid of them," Kwak said. "It's a brand new immunotherapy target."

Kwak has developed anti-cancer therapeutic vaccines to spark an immune system attack against tumors, but their effectiveness has been hindered by factors such as MDSCs that stifle immune response. "The key to taking cancer vaccines to another level is combining them with immunotherapies that target the tumor microenvironment," Kwak said.

Antibodies only bind to target cells Peptide antibodies developed by Kwak and co-discoverer, Hong Qin, Ph.D., assistant professor of Lymphoma/Myeloma, wipe out MDSCs in the blood, spleen and tumor cells of mice without binding to other white blood cells or dendritic cells involved in immune response.

"That's really exciting because it's so specific for MDSCs that we would expect few, if any, side effects," Kwak said. The team is working to develop the same target for use in humans.

With no candidate targets, the team took an objective approach by applying a peptide phage library to MDSCs, which permitted mass screening for candidate peptides -- short sequences of amino acids -- that bind to the surface of the MDSCs.

Peptide phage gathered from the MDSCs were expanded, enriched and then sequenced to identify predominant peptides. The team found two, labeled G3 and H6, that bound only to MDSCs; other candidates were eliminated because they also tied in to other types of cell.

They fused the two peptides to a portion of mouse immune globulin to generate experimental "peptibodies." Both peptibodies bound to both types of MDSC -- monocytic white blood cells, which engulf large foreign bodies or cell debris, and granulocytic white cells loaded with tiny granules.

The researchers treated mice with two types of thymus tumor with each peptibody, a control peptibody and an antibody against Gr-1. The G3 and H6 peptibodies depleted both types of MDSC in the blood and spleens of mice in both tumor models, while the Gr-1 antibody only worked against granulocytic MDSC.

Both peptibodies also wiped out the MDSCs in both types of thymic tumor and in the blood and spleen of mice with lymphoma.

Shrinking tumors, identifying alarmins To see whether MDSC depletion would impede tumor growth, they treated mice with thymic tumors with the peptides every other day for two weeks. Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with controls or the Gr-1 antibody.

Analysis of surface proteins on the MDSCs identified S100A9 and S100A8 as the likely binding targets for the two peptibodies. They're members of the S100 family of proteins, called alarmins, which are released outside the cell as a danger signal in response to inflammation.

MDSCs' mechanisms for blocking immune response are not well-characterized because they've been hard to study for lack of a targeting method, Kwak said.

Kwak and colleagues are working to extend their findings to human MDSCs.

A new class of drugs called immune checkpoint inhibitors block molecules on T cells that shut down immune response, freeing the immune system to attack tumors. The first of these drugs, ipilimumab (Yervoy®) was approved by federal regulators to treat advanced melanoma. It's the only drug ever to lengthen survival for those patients. Additional immune checkpoint inhibitors are under development.

"Immune checkpoint blockade is great," Kwak said. "There have been dramatic response rates, but those drugs also have side effects. Targeting MDSCs could provide an additional way to unleash the immune system."

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Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.

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Journal Reference:

1. Hong Qin, Beatrisa Lerman, Ippei Sakamaki, Guowei Wei, Soungchul C Cha, Sheetal S Rao, Jianfei Qian, Yared Hailemichael, Roza Nurieva, Karen C Dwyer, Johannes Roth, Qing Yi, Willem W Overwijk, Larry W Kwak. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nature Medicine, 2014; DOI: 10.1038/nm.3560