Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cedars-Sinai researchers detail events that enable brain tumors to weaken immune system

25.07.2003


In an article appearing in a special issue of the Journal of Neuro-oncology, researchers at Cedars-Sinai Medical Center’s Maxine Dunitz Neurosurgical Institute describe a complex cell-level process that allows malignant brain tumors to protect themselves by damaging the thymus, rapidly degrading the immune system. In a second article, Institute scientists identify a molecular mechanism that causes cell death of cancer-fighting lymphocytes as they infiltrate a brain tumor.



"We are dissecting and better understanding the mechanisms that enable tumors to evade destruction by the immune system. This gives us new tools in our fight against brain cancer, to essentially correct these deficits and further enhance the ability of the immune system, not only to detect but also to destroy brain tumors," said Keith L. Black, M.D., director of the Institute, Cedars-Sinai’s Division of Neurosurgery and the Comprehensive Brain Tumor Program.

In an animal study, researchers found that intracranial gliomas – aggressive brain tumors – damage the thymus, the gland responsible for the development and potency of the immune system’s T cells. As the thymus shrinks and its normal structure becomes distorted, many of the thymocytes – the "immature" cells destined to become functional T cells potentially capable of destroying a variety of antigens – undergo a process that weakens and kills them.


Thymocytes are derived from bone marrow and as they travel through the thymus they go through a natural selection process that removes the weakest and prepares the strongest to become lymphocytes that can later adapt as needed to meet a variety of immune challenges. When an intracranial glioma is present, the researchers found, the number of healthy T cells leaving the thymus is dramatically reduced, preventing a large-scale attack on the tumor.

Changes to the thymus and "recent thymic emigrant" (RTE) T cells are similar to those seen in advanced cases of AIDS, in which HIV causes thymocyte death. In glioma progression, researchers believe glucocorticoids, hormones produced by the adrenal glands, are involved in the loss of thymocytes.

The authors noted that physical stress on the body may play a significant role because it causes the release of glucocorticoids. In rats that had their adrenal glands removed to reduce the production of glucocorticoids, the damaging effects were significantly less pronounced.

This finding may also have implications for the way physicians currently treat swelling of brain tissue in patients who have brain tumors. Synthetic glucocorticoids administered to reduce intracranial pressure are highly effective for this purpose but their impact on the thymus and T cells may be further inhibiting an already embattled immune system.

Although CD8(+) cells are produced elsewhere in the body, those originating in the thymus appear to have special relevance in anti-glioma immunity, according to the study.

"It appears that these recent thymic emigrant T cells preferentially home to gliomas or they have an enhanced anti-tumor activity that allows them to home there preferentially," said Christopher J. Wheeler, Ph.D., research scientist and corresponding author on both papers.

"In a sense, we see two mechanisms working against each other," said Dr. Wheeler, "Recent thymic emigrant T cells are homing to the tumor, but there is a subversion of thymic function by the tumor itself. Therefore, while we have those cells preferentially homing – they’re enriched relative to other cells – we don’t have a lot of those cells to begin with."

According to the second paper, the tumor’s immediate environment also changes in a way that thwarts an effective tumor-infiltrating response.

The population of "types" of T cells found in aggressive, malignant tumors was out of balance compared to the response seen in benign tumors. Benign tumors had a high proportion of CD8(+) T cells compared to CD4(+) T cells, which is an indication of a strong tumor-killing immune response. In contrast, nearly all gliomas exhibited greater proportions of CD4(+) relative to CD8(+) T cells.

This manipulation of tumor-infiltrating lymphocytes does not appear to be controlled by the tumor cells themselves but at least to some extent by properties of surrounding tissue, and the ratio correlated directly with the involvement of specific protein molecules detected in nearby cells.

The suspect proteins, Fas ligand (FasL) and Fas, exist in normal brain and blood vessel lining tissue and play a role in immune system regulation. Based on this study, however, they also are expressed on tumor-associated endothelial cells where they may intercept the cancer-fighting T lymphocytes. Endothelial cells make up the lining of blood vessels.

According to the article, increasing levels of endothelial FasL correlated with decreasing proportions of tumor-infiltrating cytotoxic T lymphocytes – tumor-killing immune cells. This suggests the possibility that Fas ligand contributes to a tumor’s ability to evade the immune system.

Taken together, the studies indicate that malignant brain tumors are protected against immunity because the number of potential T cells is reduced in the thymus, and those that initially survive may later be damaged or destroyed.

Malignant gliomas continue to be considered incurable with a short length of survival, although researchers at the Institute have devised a vaccine strategy that has provided encouraging results in early trials. The treatment, called dendritic cell immunotherapy, assists the immune system in recognizing cancer cells as targets for attack, but it depends on the existence of healthy T cells to launch and sustain the immune response.

"The immune system will try to fight off a malignant brain tumor but because it does not accomplish this very effectively, we’re trying to enhance its ability with our cancer vaccine and other therapies," said Dr. Black, who holds Cedars-Sinai’s Ruth and Lawrence Harvey Chair in Neuroscience.

"We know that the strongest predictor of survival in patients with brain tumors is age. The younger immune system is better able to put up resistance than an older immune system because the thymus naturally becomes weaker and it has fewer precursors of immune cells to recruit in the fight against the tumor. We observe a strong correlation between the survival of a tumor and patient age, which is directly proportional to the number of T cells produced by the thymus."

The current studies provide insights that may lead to methods to prevent loss of T cells, repair those that become damaged, and strengthen and replenish the supply needed to contain and destroy brain tumors.

Sandra Van | EurekAlert!
Further information:
http://www.csmc.edu

More articles from Health and Medicine:

nachricht New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology

nachricht Alzheimer’s: Cellular Mechanism Provides Explanation Model for Declining Memory Performance
21.09.2016 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

Im Focus: New laser joining technologies at ‘K 2016’ trade fair

Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.

K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

Using mathematical models to understand our brain

16.09.2016 | Event News

 
Latest News

Chains of nanogold – forged with atomic precision

23.09.2016 | Life Sciences

New leukemia treatment offers hope

23.09.2016 | Health and Medicine

Self-assembled nanostructures hit their target

23.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>