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Immune checkpoint inhibitors are revolutionizing the treatment of cancer, but new research challenges the central dogma of how these drugs work. This research, published in the prestigious , shows for the first time that often-overlooked immune cells called Natural Killer (NK) cells play a crucial role in responding to checkpoint inhibitors.
鈥淐heckpoint inhibitors work by waking up the body鈥檚 own immune system and unleashing an immune attack on cancer cells,鈥 explained co-senior author Dr. , a scientist at The Ottawa Hospital and assistant professor at the University of Ottawa. 鈥淔or 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.鈥
Dr. Ardolino led the study together with Dr. David Raulet, professor at the University of California at Berkeley.
鈥淚n the cancer immunotherapy field there has been a singular focus on mobilizing anti-tumor T cells, said Dr. Raulet. 鈥淲e 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.鈥
T cells and NK cells can both recognize and kill cancer cells, but they do so in very different ways. NK cells recognize patterns of changes on cancer cells and are the immune system鈥檚 first line of defense. A T cell, on the other hand, recognizes a single abnormal molecule on a cancer cell and initiates a more focused attack.
In the current study, Dr. Ardolino and Dr. Raulet and their colleagues investigated the effect of checkpoint inhibitors in various mouse models of cancer. They found that checkpoint inhibitors could shrink tumours even in mice with no anti-cancer T cells, meaning that some other kind of cell must be responding to the checkpoint inhibitors. When the mice were depleted of NK cells, it greatly reduced or eliminated the anti-cancer effect of the checkpoint inhibitors. They also showed that NK cells produce the same checkpoint receptor molecules that T cells do, meaning they can respond directly to checkpoint inhibitors.
鈥淭his research helps solve a mystery that鈥檚 been seen in the clinic, where certain cancers are very susceptible to checkpoint inhibitors even though their T cells don鈥檛 seem to be activated,鈥 said co-lead author Jonathan Hodgins, a PhD student at The Ottawa Hospital and the University of Ottawa. 鈥淚f we鈥檙e right, NK cells are probably being activated in these patients.鈥
The researchers are now investigating approaches to further enhance the cancer-killing ability of NK cells.
鈥淢y dream is that when people come to the hospital with cancer, we鈥檒l 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,鈥 said Dr. Ardolino. 鈥淭hen we would give the patient the immunotherapy treatments that is most likely to work for them.鈥
Dr. Ardolino, a native of Italy, worked in Dr. Raulet鈥檚 lab in California before he was recruited to The Ottawa Hospital and the University of Ottawa in 2016.
Ottawa is a leader in the field of cancer immunotherapy, particularly in the emerging field of NK cell research. For example, Dr. Rebecca Auer discovered that surgery suppresses NK cells and can therefore help cancer spread. She鈥檚 leading several clinical trials to test novel approaches to reverse this. Dr. Ardolino, Dr. Auer, Dr. and others are also investigating the use of viruses to enhance cancer-killing by NK cells. The team is also interested in creating genetically engineered NK cells to attack cancer cells, similar to CAR-T cells.
鈥淣K cells are the new T cells鈥 said Dr. Auer, a surgical oncologist and director of cancer research at The Ottawa Hospital and associate professor at the University of Ottawa. 鈥淭his field is exploding, and we鈥檙e poised to be at the forefront.鈥
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