New Strategy Aims to ‘Soften Up’ Tumors for Attack by Natural Killer Cells

Key Takeaways:

  • Natural Killer cells show promise as a potential immunotherapy for certain cancers, but these cells often lack potency or durability when administered to patients.
  • A new treatment strategy emerging is to make the targeted cancer cells more vulnerable to an NK cell attack.
  • This approach pairs BH3 mimetic drugs with NK cells in a synergistic combination to force cancer cells to self-destruct.

Scientists are stepping up efforts to deploy natural killer (NK) cells — the body’s first responders against infected and malignant cells — to combat cancer. Treatment using NK cells from healthy donors has shown promise, but currently successes have been limited and the cells lack staying power in the body. While some researchers are working to improve the potency and endurance of NK cells, a team of Dana-Farber scientists led by Tony Letai, MD, PhD, has taken a different tack.

Instead of concentrating entirely on the immune killer cells, Letai’s team has devised a strategy for “softening up” tumor cells — making them “easier targets for NK cells, thus potentially accelerating NK-mediated killing.” Letai adds: “If you want to make immune cells work better, we’re saying that you need to focus on the cancer cell as well as the immune cell.”

The scientists describe this strategy in a report in CELL, whose first author is Rongqing ‘Aaron’ Pan, PhD, a post-doctoral fellow in the Letai lab. Letai is the senior author.

Rongqing ‘Aaron’ Pan, PhD, a post-doctoral fellow in the Letai lab.
Rongqing ‘Aaron’ Pan, PhD, a post-doctoral fellow in the Letai lab.

NK cells are a rapidly acting type of white blood cell belonging to the innate immune system. They respond quickly to virus-infected cells and also to tumor cells, without being directed by other components of the immune system. When they contact target cells, they secrete granzymes — enzymes that enter the cells and trigger apoptosis — self-inflicted cell death. There are multiple pathways by which apoptosis works, and the researchers first identified which one was triggered by NK cells: it was the so-called mitochondrial apoptosis pathway. By adding NK cells to cancer cells in the laboratory, the researchers observed that the NK cells triggered apoptosis very quickly – within a matter of hours.

In addition, this insight told the scientists that it could be possible to augment the killing effect of NK cells by combining them with BH3 mimetics — drugs that counteract the survival mechanism of cancer cells and push them closer to the brink of self-destruction by apoptosis. Several drugs based on BH3 mimetics — including the first-in-class venetoclax — are in use or are in development.

Letai and his colleagues have devised and honed a testing method called “BH3 profiling” that can reveal the extent of “priming” in cancer cells — that is, how close or far away the cells are from the point at which apoptosis can be easily triggered to cause them to self-destruct. Their experiments showed that BH3 mimetics, when applied to cancer cells, helped “prime” them — that is, push them toward the point of apoptotic death — so that subsequent contact with NK cells was more likely to kill the cancer cells. BH3 profiling can also be used to help identify which of several available BH3 mimetic drugs would be most likely to be effective against an individual patient’s tumor. 

The concept hasn’t yet been tested in human trials. But the investigators say that through the results of their laboratory tests, they were able to demonstrate that BH3 mimetics and NK cells can work together to kill cancer cells and suppress tumor growth, and that BH3 profiling can be used to choose which BH3 mimetic would combine well with NK cells in treating an individual cancer. In addition, they say, “this approach may be adaptable to T cell-based immunotherapies as well.”