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


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!
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