Stanford biologists found that ovarian cancer cells evade the immune system by signaling that they are part of a developing fetus, according to an August research study published in “Cell Reports.”
Lead researcher and assistant professor of urology at Stanford Medicine Wendy Fantl and her team researched and sorted cells present within ovarian cancer tumors to understand the mechanism behind the quick growth of these tumors.
Close to 90% of ovarian cancer patients will survive for no more than five years, according to co-author and urology postdoctoral scholar Antonio Delgado-Gonzalez, who is part of the Fantl Lab. Delgado-Gonzalez also said that ovarian tumors typically present asymptomatically, making them difficult to detect early on.
“This is a disease in great need of new effective treatments,” Fantl said. “While women may initially respond to treatments such as chemotherapy, most of them will relapse so we really wanted to understand what was going on.”
Fantl and her research team analyzed over 800,000 cancer cells in 17 patients who had been newly diagnosed with ovarian cancer. They used a new technique called CyTOF developed by the lab of microbiology and immunology professor Garry Nolan. CyTOF makes it possible to analyze each intact cell as opposed to groups of similar cells, which allows the researchers to identify rarer subsets of cells. Each cell was sorted into a different category based on which proteins it expressed.
“If you think about the tumor itself, it is a very complex tissue. You are going to find cells that give rise to the tumor, the resident immune cells and more,” co-author and microbiology instructor Ermenlinda Porpiglia said. “This single-cell analysis, or CyTOF, allows you to identify individual cell types.” Resident immune cells refer to cells from the patient’s immune system.
Some of the cells in the immune system’s line of defense, termed natural killer cells, typically recognize anything foreign within the body and proceed to kill it, according to co-author and Stanford pathology instructor Kevin Kolahi. A developing fetus would be viewed as a foreign object if this line of defense was not suppressed.
However, decidual natural killer cells contain a unique marker.
“These [decidual] natural killer cells create an environment that is suppressive so the mother immune system does not attack the fetal immune system,” Kolahi said.
Ovarian cancers exploit this mechanism. Researchers found a high number of cancer cells with a protein called CD9 present on their surface within the tumor, similar to the decidual natural killer cells that arise during a pregnancy. The cancer cells transfer CD9 to the natural killer cells within the body through a process called trogocytosis. This suppresses the immune response of the natural killer cells similar to how immune response is mediated when mothers have a developing fetus.
The 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 can become less effective,” Porpiglia said.
These findings have important implications for the potential development of new forms of immunotherapy and possible screening tools. Fantl has procured another grant to continue her work. She will work with a collaborator in Milan, Italy to determine if detection of natural killer cells with CD9 is possible in earlier stages of ovarian cancers.
“The work has definitely spawned many avenues for further research, and I’m excited about that and for more mechanisms of immunotherapy to be discovered,” Fantl said.