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Cancer Stem Cells Suppress Immune Response Against Brain Tumor

ScienceDaily, January 17, 2010

Cancer stem cells may be viewed as the root of a tree:  when you cut the tree if you leave root, the tree will grow back.  Conventionally chemotherapeutic approaches have been focused on cutting the tree but forgetting about the root.  This explains the overall poor success in treatment of many cancers in that the cancer comes back after a period of remission.  The discovery of cancer stem cells has generated a shift in our thinking of cancer.  Specifically, it was found that cancer stem cells are resistant to many types of chemotherapies, and that drugs that target the cancer stem cell do not necessarily have effects on cancer cells that are not stem cells.

Glioblastoma multiforme is an aggressive type of brain cancer in which the stem cell compartment has been relatively more studied than in other types of cancer.  New drugs or combination therapies are needed, because after decades of research, little progress has been made in treating this condition. Even with the best of care patients with glioma survive an average of 14 months.

It is known that if one extracts a glioma patient biopsy and implants the cells in a mouse that lacks an immune system, the cells expressing the marker CD133 cause the tumor to grow in the mouse, whereas the cancer cells that lack this marker undergo a period of transient multiplication but are not capable of reproducing the whole tumor.  While significant amount of research has focused on how cancer stem cells are different than cancer cells that are not stem cells, relatively little work has gone into identifying immunological properties of cancer stem cells.

Theoretically, it would make sense that cancer stem cells have different immunological properties.  Non-cancer stem cells have many things in common with cancer stem cells.  This includes expression of markers such as CD133, ability to pump out toxic drugs, and relative propensity for areas that are low in oxygen concentration.  Immunologically, stem cells seem to be immune suppressive since the stem cell is sensitive to oxidative stress, and immune system activation usually results in increased oxidative stress. 

Scientists at the University of Texas M. D. Anderson Cancer Center report in a medical paper (Wei et al. Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res. 2010 Jan 15;16(2):461-73) that cancer stem cells actually suppress the immune system more potently as compared to cancer cells that are not stem cells.  They found that cancer stem cells were capable of blocking activation and multiplication of T cells.  T cells are an important part of immunological defense against cancer: mice genetically engineered to have deficient T cells have faster growing tumors, and patients who receive an organ transplant and as a result of immune suppressive medication have poor T cell function are at a higher risk of cancer.  Additionally, it was demonstrated that the cancer stem cells possess the ability to induce generation of T regulatory cells.  These are a type of T cell that suppresses activation of other T cells.  T regulatory cells play an important role in the ability of cancer to escape immune recognition.  This is known from animal studies in which depletion of T regulatory cells by antibodies or drugs is associated with higher anti-tumor immunity.  In human studies numerous correlations have been made between higher number of T regulatory cells and shorter survival.  Depending on tissue culture conditions, cancer stem cells have also been demonstrated to directly induce death of T cells.  The investigators found that these immune-changing activities of cancer stem cells were caused by the molecules B7-H1 and galectin-3.  When the cancer stem cells were treated with chemicals to induce them to differentiate into cancer cells that are not stem cells, the immune suppressive properties were diminished.   

We've known for years that glioblastoma and cancer patients in general have impaired immune responses," said senior author Amy Heimberger, M.D., an associate professor in M. D. Anderson's Department of Neurosurgery. "Our research uncovers an important mechanism that shows how that happens. The cancer stem cells inhibit T cell response, and it is these T cells that recognize and eradicate cancer."

One of the implications of this research is that cancer stem cells may specifically block the part of the immune system that is responsible for killing the cancer stem cells, while allowing other parts of the immune system to remain intact.  One of the major mysteries of tumor immunology has been that many cancer patients still have a productive immune response against non-cancer proteins, but for some reason the immune response does not eradicate the cancer. 

"There are multiple research groups around the country, including ours, trying to develop vaccines or other immunotherapeutics against glioma stem cells," Heimberger said. "Now we have to be cognizant that the stem cell may deliver a fatal blow back to the immune system, which will help us understand how to design immune-based therapies."

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