A study by researchers at Karolinska Institutet, published in Cancer Immunology Research, has found that a powerful subset of immune cells—adaptive natural killer (aNK) cells—may be especially effective at targeting ovarian tumors. These cells appear to “remember” and respond to cancer-specific signals, showing promise as a new type of cell-based immunotherapy for hard-to-treat cancers, such as high-grade serous ovarian cancer (HGSOC).
Natural killer (NK) cells are part of the body’s innate immune system and serve as an early line of defense against infections and cancer. Unlike T cells, which are known for their ability to remember specific targets, NK cells were long thought to be short-lived and non-specific. But newer research has identified a special population—adaptive NK cells—that can persist over time and respond more effectively when they re-encounter certain triggers, such as viruses or, as this study suggests, cancer.
In this work, the Karolinska team asked whether aNK cells could mount a memory-like immune response to ovarian tumors, helping them seek out and kill cancer cells more precisely than standard NK cells. Using patient tumor samples, laboratory experiments, and gene expression data, the researchers demonstrated that aNK cells are indeed present within ovarian tumors and can respond to them with high specificity.
Unlike conventional NK (cNK) cells, aNK cells appeared to home in on cancer cells more effectively, even in the harsh, immune-suppressive environment of the tumor. Their cancer-killing activity was further enhanced when they were “primed” within the tumor microenvironment by dendritic cells, immune cells that help present antigens to the immune system. This priming process likely helps aNK cells recognize and remember the tumor.
The team also found that aNK cells used specific receptors and signaling pathways to infiltrate the tumor and avoid being shut down by the cancer. One key difference: aNK cells had low levels of NKG2A, a receptor that tumors often exploit to deactivate immune responses. This may help aNK cells remain active in tumors where conventional NK cells lose their effectiveness.
When re-exposed to tumor cells, aNK cells responded with a burst of inflammatory signals and cancer-killing molecules, behaving much like memory T cells. They also showed signs of expanding in number and migrating to the tumor site, reinforcing the idea that these cells are capable of long-term, targeted activity.
“These findings suggest that aNK cells could serve as potent agents in NK cell-based immunotherapies, particularly in solid tumors like HGSOC, where they resist immunosuppressive signals and maintain robust anti-tumor activity,” the authors write.
To understand how this memory-like response develops, the researchers built a model system in the lab that mimicked how dendritic cells might activate aNK cells in the body. The results confirmed that this interaction was key to triggering both their memory-like behavior and cancer-killing activity.
While adaptive NK cells have previously been linked to viral infections and blood cancers, this study is among the first to demonstrate that they can also respond to solid tumors, such as ovarian cancer. The researchers believe these findings could lay the groundwork for new therapies that harness the unique capabilities of aNK cells.
“The study also challenges previous perceptions of NK cells, which have historically been considered only innate immune cells with no memory function against cancer,” says senior author Dhifaf Sarhan, senior lecturer at the Department of Laboratory Medicine, Karolinska Institutet. “This opens new opportunities for the development of innovative immunotherapies.”
Current NK cell therapies have faced challenges, particularly in expanding the right types of cells and ensuring they effectively reach and kill tumor cells. This study points to new directions—such as combining aNK cells with dendritic cell-based vaccines or refining lab-grown NK cell therapies—that may improve outcomes in cancers that resist standard treatments.
The team’s next steps are to develop methods that increase the number and activity of aNK cells in patients, followed by clinical trials to evaluate their effect on patient survival rates.
