Stanford biologists have discovered that ovarian cancer cells elude the immune system by signaling that they are part of a developing fetus, according to an August study published in “Cell Reports.”
Principal investigator and assistant professor of urology at Stanford Medicine Wendy Fantl and her team researched and sorted cells found in ovarian cancer tumors to understand the mechanism behind the rapid growth of these tumors.
According to co-author and postdoctoral researcher in urology Antonio Delgado-Gonzalez, who is part of the Fantl Lab, nearly 90% of patients with ovarian cancer will survive a maximum of five years. Delgado-Gonzalez also said that ovarian tumors usually present asymptomatically, which makes them difficult to detect early on.
“It is a disease that is in dire need of new, effective treatments,” Fantl said. “While women may initially respond to treatments like chemotherapy, most of them will relapse, so we really wanted to understand what was going on. “
Fantl and his research team analyzed more than 800,000 cancer cells in 17 patients who had recently been diagnosed with ovarian cancer. They used a new technique called CyTOF developed by the microbiology lab and professor of immunology Garry Nolan. CyTOF allows each intact cell to be analyzed as opposed to groups of similar cells, allowing researchers to identify rarer subsets of cells. Each cell was put into a different category based on the proteins it expressed.
“If you think of the tumor itself, it’s a very complex tissue. You’re going to find cells that give birth to the tumor, resident immune cells and more, ”said Ermenlinda Porpiglia, co-author and instructor in microbiology. “This single-cell analysis, or CyTOF, allows you to identify individual cell types.” Resident immune cells refer to cells of the patient’s immune system.
Some of the cells in the immune system’s line of defense, called natural killer cells, typically recognize anything foreign in the body and proceed to destroy it, according to Stanford co-author and pathology instructor Kevin Kolahi. A developing fetus would be considered a foreign object if this line of defense were not removed.
However, natural decidual killer cells contain a unique marker.
“Those [decidual] natural killer cells create a suppressive environment so that the mother’s immune system does not attack the fetal immune system, ”Kolahi said.
Ovarian cancers exploit this mechanism. Researchers have found a high number of cancer cells with a protein called CD9 present on their surface in the tumor, similar to the natural decidual killer cells that appear during pregnancy. Cancer cells transfer CD9 to natural killer cells in the body through a process called trogocytosis. This suppresses the immune response of natural killer cells in the same way that the immune response is mediated when mothers have a developing fetus.
Tumor cells can continue to grow and form more aggressive tumors by evading the immune system.
“With natural cells becoming less effective, the immunotherapy itself may become less effective,” Porpiglia said.
These findings have important implications for the potential development of new forms of immunotherapy and possible screening tools. Fantl got another grant to continue his work. She will work with a collaborator in Milan, Italy, to determine whether detection of natural killer cells with CD9 is possible in the early stages of ovarian cancer.
“The work has certainly opened up many avenues for new research, and I’m excited about this and the discovery of more mechanisms for immunotherapy,” Fantl said.