New research in mice reveals why natural killer cells, normally effective at hunting cancer, are sometimes stopped in their tracks.
Natural killer cells, famous for their prowess at wiping out cancer and virus-infected cells, are not always effective, particularly when it comes to fighting tumors. Now, research in mice points to a possible reason: when NK cells “bite off” part of cancer cells’ membranes, they can ingest a serving of protein that renders them useless.
NK cells, also known as large granular lymphocytes, engage tumor cells in a process called trogocytosis, which involves stealing part of their target’s membrane and integrating it into their own. The new study, published today (April 13) in Science Advances, shows in mice with leukemia that this nibble sometimes comes with a side of PD-1, a protein that inhibits NK cell activity, allowing the cancer cell to escape.
When an immune cell such as an NK cell or a T cell encounters PD-1 on the surface of a cancer cell, its activity is subdued. PD-1 is thus a common target of cancer immunotherapies, which aim to rev up the body’s own defenses against the disease.
Study coauthor Michele Ardolino, a cancer immunologist at the Ottawa Hospital Research Institute and the University of Ottawa, explains that the findings resolve a mystery in the existing literature on PD-1 and cancer. Prior to the new paper, some recent studies found small amounts of PD-1 on the surface of NK cells, suggesting that perhaps the NK cells were producing PD-1 on their own, but others found none. “When you see protein on the surface of a cell, you’re inclined to predict it would produce it,” Ardolino tells The Scientist. “Any scientist would tell you that they would think that’s the way it would work.”
Ardolino had encountered trogocytosis in prior work, so he set out to explore whether the process could explain how natural killer cells ended up with PD-1 on their membranes. The study authors used a mouse model that doesn’t produce PD-1 at all, injected them with PD-1–containing cancer cells, and found that the mice still responded to a PD-1 blocking medication. The fact that the mice’s immune response improved after PD-1 blocking indicates that the protein was present in their system and that the cancer, not any of the mice’s NK cells, must have produced it. The researchers also stained PD-1 in mouse cells in a dish and found that only NK cells cocultured with PD-1–expressing cancer cells had the protein on their membranes. Finally, the researchers stained NK cells taken from the bone marrow of human cancer patients, most of whom had multiple myeloma, and saw that NK cells with PD-1 on their surfaces also had other cancer cell markers, suggesting that they obtained both through trogocytosis. Ardolino says the results suggest that cancers likely evolved the ability to express PD-1 on their surface in response to pressure from the hungry NK cells.
“This is quite surprising to observe that trogocytosis can be so powerful!” Laurence Zitvogel, an oncoimmunologist who studies NK cells at University Paris Saclay and Gustave Roussy Cancer Center in France and who didn’t work on the new study, tells The Scientist over email. She adds that the paper was very thorough in showing that NK cells obtain PD-1 through trogocytosis rather than producing it themselves.
Going forward, Zitvogel says she hopes researchers uncover more details about how much PD-1 is produced in various human cancers and how much is needed to prevent NK cell activity. But Ardolino suggests that PD-1 is just scratching the surface.
“What are the molecules that tumors select to give to NK cells?” he says. “We stumbled on PD-1, literally, looking at this leukemia tumor model. But we know that NK cells do a lot of trogocytosis with other tumor cells,” so there may be additional cancer-related molecules they ingest.
Clarification (April 14): The original headline on this article, “Why Chomping on Cancer Cells Can Thwart Immune Cells’ Attack,” was changed to avoid ambiguity.