Cancer's shield seen, stripped

Researchers have identified how cancer escapes detection by the immune system -- support cells surrounding a tumor protect it from triggering an immune reaction. The research, published this week in linkurl:Science,;https://www.sciencemag.org/ may ultimately provide a new therapeutic target to activate the body's natural defenses against malignant cells. "The beauty of this article is that it clearly connects certain stromal cells of the tumor microenvironment to the immune system," said linkurl:Hans Schreiber,;https://biomed.uchicago.edu/common/faculty/schreiber.html an immunologist at the University of Chicago who was not involved in the study. "It was very well done."

Macrophages of the immune system
attacking a cancer cell
linkurl:Susan Arnold;https://commons.wikimedia.org/wiki/File:Macs_killing_cancer_cell.jpg

Researchers have long wondered how cancer evades attacks by the immune system, trained to recognize and destroy all foreign material. In the past, even when an immune response is mounted in an animal with cancer, the tumor itself remains relatively unscathed, since neighboring immune cells fail to attack. "It was something going on inside the tumor that was suppressing the immune reaction," said linkurl:Douglas Fearon,;https://www.immunology.cam.ac.uk/directory/profile.php?DFearon an immunologist at the University of Cambridge and senior author on the paper. Cancer cells sit in a bed of nonmalignant connective tissue called stroma. Fearon and colleagues hypothesized that a subset of stromal cells expressing fibroblast activation protein (FAP) might be involved in keeping the immune system at bay, since FAP expressing cells are also present in the uterus, placenta, and areas of chronic inflammation, all locations where the body is trying to subdue or control an immune response. The team bred transgenic mice with a genetic switch to kill FAP expressing cells when exposed to diptheria toxin and injected the mice with tumors. Two to three weeks later, when the tumors were well established, the researchers eliminated the animals' FAP+ cells. Within 48 hours, the mice had mounted an immune response that killed 80 to 90 percent of the tumors. As a control, the researchers performed the same experiment in mice without an immune system, and removing the FAP+ cells had no effect on the tumors. "We had to combine both depleting FAP+ cells and an immune response to the tumor," said Fearon. "That proved that the tumor death caused by [loss of] FAP+ cells was mediated by the immune system."The team is planning to validate their findings in a spontaneous tumor mouse model developed by linkurl:researchers at Cancer Research UK,;https://www.cambridgecancer.org.uk/research/loc/cambridge/ccri/tuvesond/?view=CRI&source=research one that better models tumor development in humans. The paper demonstrates that FAP+ stromal cells are an important target for cancer drugs, said Schreiber, who wrote an accompanying perspective in Science. But though antibodies already exist for FAP, the challenge will be targeting drugs to the cells without affecting the many other nonmalignant cells that express FAP, he cautioned.But if researchers can determine how the FAP+ cells are getting to tumors or how they suppress an immune response, they may be able to either block the cells from getting to a tumor or from suppressing the immune system once there. "At least now there is a very specific cell type we can analyze that might be accounting for suppressing immune reactions in a tumor," said Fearon. "It's a step."Kraman, M. et al., "Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-alpha," Science, 330:827-30, 2010.
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[2nd February 2008]