CRI-Funded Study Highlights the Importance of Natural Killer Cells in Immunotherapy

Immunotherapy, which targets patients’ immune systems to help them control or eliminate cancer, has begun to revolutionize the treatment of cancer. Checkpoint inhibitor immunotherapies that target the PD-1/PD-L1 pathway have been especially effective for many patients, and are now FDA approved in eleven major types of advanced cancer.

While the success of these immunotherapies has been largely attributed to their ability to “release the brakes” on “killer” T cells, a new study funded by the Cancer Research Institute revealed that these immunotherapies can also enhance the cancer-fighting capabilities of immune cells known as natural killer (NK) cells. 

This work was first published Monday in the Journal of Clinical Investigation, and was led by co-senior authors Michele Ardolino, PhD, a scientist at The Ottawa Hospital and an assistant professor at the University of Ottawa, and David H. Raulet, PhD, the Esther and Wendy Schekman Chair in Basic Cancer Biology at the University of California, Berkeley.

“Checkpoint inhibitors work by waking up the body’s own immune system and unleashing an immune attack on cancer cells,” noted Ardolino, who was first funded by the Cancer Research Institute (CRI) in 2013 while he was a postdoctoral fellow in Raulet’s lab. “For many years, everyone assumed that checkpoint inhibitors targeted immune cells called T cells. But our research shows that they also target Natural Killer cells and these cells play a key role in the how this treatment works.”

Michele Ardolino, PhD

As part of their work, which also involved current CRI CLIP investigator John C. Bell, PhD, the researchers used a mouse cancer model that exhibits diminished expression of the class I major histocompatibility complex (MHC), an important group of proteins that enable T cells to precisely identify and target cancer cells. This relative lack of class 1 MHC appeared to prevent T cells—but not NK cells—from eliminating the cancer cells.

Indeed, even in mice that lacked T cells entirely, checkpoint immunotherapy was able to promote the elimination of tumors; however, those benefits were either reduced or eliminated when NK cells were also depleted. Bolstering their case that NK cells contributed to these responses was the fact that the NK cells within tumors were found to express the PD-1 immune checkpoint receptor that is blocked by the checkpoint immunotherapy treatment. The research team also observed that NK cells played a role in protecting mice against tumor development even in the absence of immunotherapy.

“In the cancer immunotherapy field there has been a singular focus on mobilizing anti-tumor T cells,” added Raulet, who himself was first funded as a CRI investigator in 1986 and received CRI’s highest scientific honor, the William B. Coley Award, in 2002. “We believe that NK cells have an important place at the table. Checkpoint therapy combined with other NK-directed immunotherapies may enable us to target many types of tumors that are currently non-responsive to available therapies.”

David H. Raulet, PhD 

To that end, Ardolino and Raulet aren’t the only CRI scientists who are exploring how NK cells might be able to improve the success of current immunotherapies. Mark J. Smyth, PhD, a CRI CLIP investigator at the QIMR Berghofer Medical Research Institute in Australia; Lydia Lynch, PhD, a CRI CLIP Investigator at Brigham and Women's Hospital and Harvard Medical School; Nicholas Huntington, PhD, and Sandra Nicholson, PhD, CRI CLIP Investigators at the Walter and Eliza Hall Institute of Medical Research in Australia; and Avishai Shemesh, PhD, a CRI postdoctoral fellow in the lab of Lewis Lanier, PhD, at the University of California, San Francisco, are also working in this promising area of research.

Hopefully, their investigations continue to improve our understanding of NK cell activity in the context of cancer and, when combined with other breakthroughs being made in the cancer immunotherapy space, pave the way for the development of novel treatment approaches that can benefit even more patients in the clinic.

“My dream is that when people come to the hospital with cancer, we’ll be able to take a biopsy and determine not only the mutations in their cancer, but also profile how their immune system is interacting with their cancer,” declared Ardolino. “Then we would give the patient the immunotherapy treatments that is most likely to work for them.”

NK cells attacking tumor. Credit Michele Ardolino Brian Weist