Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Lab study defines and blocks mechanism that lets brain tumors sidetrack immune response

25.10.2004


Researchers at Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute have described an immune-disruptive process driven by an enzyme that is overexpressed in the cells of many types of tumors, including malignant brain tumors called gliomas.
Blocking the enzyme’s expression in laboratory tests interrupted the series of cell-level events and led to the development of cells capable of launching an immune response. This finding supports the suggestion that medications attacking the enzyme may boost the immune system’s ability to recognize and target gliomas.

Results of the study on cyclooxygenase-2 (COX-2) appear in the October 1 issue of the Journal of Immunology. While COX-2 inhibition has been considered an attractive anti-cancer strategy, results of earlier studies on a variety of tumors have been inconsistent, puzzling and sometimes seemingly contradictory. Furthermore, because COX-2 is a complex enzyme that is affected by a variety of conditions and biochemical substances, many of its mechanisms and effects are not clearly understood.


In the article, Institute researchers describe COX-2’s detrimental influence on dendritic cells – the immune system cells responsible for detecting foreign matter and eliciting an immune response. Dendritic cells, highly specialized "antigen-presenting cells," pick up debris left behind when cells die. When they take up and process debris from tumor cells, they should present these antigens to cytotoxic T lymphocytes (CTL), cancer killing cells, instructing them to attack the tumor cells.

If functioning properly, the dendritic cells would induce the production of a protein called interleukin-12 (IL-12), which prompts the immune system’s CD4+ T lymphocytes to launch a T helper type 1 (Th1) response – attack mode. Lymphocytes would swarm to the source of the antigens and attack the tumor cells.

Instead, the researchers found, COX-2 and a hormone-like substance it synthesizes, prostaglandin E-2 (PGE-2), set in motion a series of interactions that changed the message of the dendritic cells and the function of the T cells. Instead of inducing the production of IL-12, the dendritic cells prompted the overproduction of IL-10 and transforming growth factor-beta (TGF-â). Both of these substances spur "regulatory" responses – making lymphocytes "tolerant" of the antigens and suppressing an attack.

According to John S. Yu, MD, the study’s principal investigator, "COX-2 expression by tumors may make them invisible to the immune system. By using COX-2 inhibitors, these tumors may become more detectable and therefore more vulnerable to destruction by the immune system. We plan to exploit these findings by adding COX-2 inhibitors like Celebrex® (celecoxib) to our clinical trials for brain tumors."

"We have recognized for some time that defects in the process of antigen presentation were involved in the impaired cellular immunity seen in patients with glioma," said Keith L. Black, MD, director of the Institute, Cedars-Sinai’s Division of Neurosurgery and the Comprehensive Brain Tumor Program. "Our findings indicate that COX-2 and PGE-2 expressed in glioma may be key factors in the down-regulation of tumor-killing immunity at the level of antigen presentation. Immature dendritic cells exposed to gliomas that overexpress COX-2 become mature dendritic cells that produce significant levels of IL-10 and decreased levels of IL-12. This leads to suppression of cellular immune responses at the site of the tumor and systemically."

The study was conducted using two established glioma cell lines and tumor cells taken from a patient at Cedars-Sinai. "One of the intriguing findings was that helper cells isolated from the bloodstream of a glioblastoma patient predominantly displayed a regulatory response against the patient’s glioma cells. This points to the existence of an underlying regulatory bias in the circulating T cells of patients with malignant glioma," said Dr. Yu, co-director of the Comprehensive Brain Tumor Program.

"Previous studies and experience have suggested that CD4+ T cells taken from glioma patients have markedly impaired tumoricidal responses," he added. "We now propose that this is secondary to a skew in antigen presentation away from a tumoricidal Th response and toward a regulatory response, resulting from the effects of PGE-2 by COX-2 on dendritic cells exposed to these tumors."

By blocking the COX-2 expression in gliomas before dendritic uptake, the tumor-killing Th1 response can be restored, the research team found. "We suggest that high levels of dendritic cell IL-12 secretion and a Th1 response can be induced following COX-2 inhibition," Dr Black said. "These findings support the use of COX-2 inhibitors as a means of promoting Th1-directed tumor antigen presentation in clinical trials of dendritic cell-based vaccines."

Over the past several years, Institute researchers have developed and fine-tuned an experimental vaccine therapy against deadly gliomas that hinges on culturing a patient’s glioma cells with his or her own dendritic cells. When these new dendritic cells are reintroduced into the body, they are better able to recognize and present glioma antigens. As new discoveries are made about the immune system and the genetic makeup, cellular components, and biochemical mechanisms of tumors, additional potential therapies are devised and integrated to boost immune response and capitalize on vulnerabilities of cancer cells.

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

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>