NK Cells Respond to Checkpoint Blockade

Natural killer (NK) cells may play an important role in antitumor response to immune checkpoint blockade, according to a recent study (J Clin Invest 2018;128:4654–68). Using mouse models, researchers established that NK cells respond to PD-1 and PD-L1 inhibitors, information that could be used to develop immunotherapies that mobilize NK cells against cancer.

Cancers that are responsive to immune checkpoint inhibitors, such as melanoma and lung cancer, often have high MHC class I/II expression or mutation rates, making them a target for T cells, notes Michele Ardolino, PhD, of the Ottawa Hospital in Canada, co–senior author. However, that isn't always the case.

“It is well known that Hodgkin lymphoma patients are very responsive to checkpoint blockade, and this is sort of a conundrum,” Ardolino says, because their tumors have a loss of MHC class I expression. Consequently, he and his team decided to investigate whether “there was a T cell–independent response that was initiated by immune checkpoint blockade,” with earlier research pointing to NK cells.

In a previous paper, the researchers investigated the activity of NK cells in tumors lacking MHC class I expression (J Clin Invest 2014;124:4781–94). In their recent study, the researchers found that when they treated mice that had tumors with low MHC class I expression—and were thus invisible to T cells—with PD-1 or PD-L1 inhibitors, the mice had reduced tumor growth and improved survival. However, the effect disappeared when they eliminated NK cells, “which to us suggested that in this tumor model, we could see a therapeutic effect that was linked to the presence of NK cells,” Ardolino says.

Using various mouse models, the team also established that PD-1 is expressed by some NK cells present in the tumor microenvironment, and those NK cells are more activated and more responsive to PD-1 inhibitors than cells that don't express PD-1.

Finally, the researchers eliminated PD-L1 expression in mouse models of colon cancer and triple-negative breast cancer. They found that the PD-L1–deficient tumors did not grow as quickly as those that expressed PD-L1, though tumor growth was somewhat faster when the researchers depleted either T cells or NK cells. However, when they eliminated both T cells and NK cells, the tumors lacking PD-L1 grew more quickly than those expressing PD-L1. “Both T cells and NK cells seem to be playing a role in the response of these tumors, and both of them seem to be inhibited by the presence of PD-L1,” Ardolino explains.

“We think that this study really provides evidence that we may be able to use checkpoint blockade to help mobilize NK cells for immunotherapy,” says co–senior author David Raulet, PhD, of the University of California, Berkeley. He adds that NK cells may be a good target for immunotherapy because “they're very much like T cells: They kill by the same types of mechanisms, they're regulated by some of the same signals, including checkpoint receptors, and yet their recognition is different. Many of the types of tumors that may be resistant to T cell–focused immunotherapies will be sensitive to NK-based therapies.”

For Jeffrey Miller, MD, deputy director of the University of Minnesota's Masonic Cancer Center in Minneapolis, who was not involved in the study, it “highlights the importance of immune checkpoints and goes beyond T cells, implicating the PD-1 axis as important for NK cells in the tumor microenvironment.”

André Veillette, MD, of the Montréal Clinical Research Institute in Canada, who was also not connected to the research, sees it as part of a larger trend. “There's this rejuvenation in interest in NK cells as really bona fide players and serious contenders for being used for antitumor immunity,” he says. –Catherine Caruso

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.