Cancer immunoresistance linked to loss of tumor suppressor gene
Cancer immunoresistance may be partially due to loss of a well-known tumor suppressor gene, according to new research led by Andrew T. Parsa, MD, PhD, assistant professor of neurological surgery at the University of California, San Francisco.
The findings are reported today (December 10) online and are scheduled to appear in the January issue of Nature Medicine.
It has been known for a long time that cancer cells have many different ways to avoid the immune system, including the common strategies of hiding proteins that are normally expressed on the cell surface or making proteins that act to suppress immune responses, according to Parsa. Some researchers believe that immunoresistance may contribute to cancer progression and development, he added.
Over the past four years, Parsa’s lab has focused on trying to understand how specific mutations associated with high grade glioma correlate with immunoresistance. Malignant glioma is among the deadliest types of brain cancer for which there currently is no effective treatment.
“My colleague James Waldron and I began screening different cell lines for mutations and trying to match these mutations up with proteins that suppress the immune system,” Parsa said.
The researchers began to see an interesting trend. Glioma cells with mutation in a specific gene called the phosphatase and tensin homolog gene, or PTEN, seemed more resistant to the immune system than glioma cells with normal PTEN function. Determining the mechanism responsible for the immunoresistance proved more difficult.
“Fortunately, Russ Pieper’s lab here at UCSF had developed a model that took normal human astrocytes and made them act like a malignant glioma. This allowed us to study the effects of PTEN mutation in a very well controlled manner,” Parsa said.
In glioma patients who have lost PTEN function, the tumor cells were found to express high levels of B7-H1, a protein that contributes to immunoresistance. According to Parsa, high levels of B7-H1 on a cancer cell can be thought of as a protective barrier, and T-cells that come in contact with B7-H1 positive cancer cells are ineffective.
Many types of genetic mutation can give rise to a brain tumor, he explained, “but with this particular type of mutation—the loss of PTEN function and the expression of B7-H1-- the immune system will have a harder time killing the cancer.”
The results of Parsa’s work may have implications beyond brain tumors. Loss of PTEN function is found in many types of cancers, including prostate and breast. Emerging therapies that rely on the immune system to fight cancer could potentially be more or less effective based on PTEN function.
“Immunotherapy for cancer has been effective in some patients but not in others. It’s possible that this link between PTEN loss and B7-H1 expression is responsible. We need to look at this further,” said Parsa.
Co-authors of the study were James Waldron, Amith Panner, Ian Parney, Kristine Cachola, Joseph Murray, Jeffrey Barry, Courtney Crane, Tarik Tihan, David Stokoe, and Russell O. Pieper, all from UCSF; Paul Mischel from UCLA; and Michael Jensen from City of Hope, Duarte, Calif.
The research was supported by grants from the National Institute of Neurological Disorder and Stroke, Brain Specialized Programs of Research Excellence (SPORE) of the National Cancer Institute, the Seibrandt Vaccine Fund, and the Khatib Research Foundation.
UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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