New research reveals a mechanism explaining why natural kills (NK) cells, known to have a major role in eliminating cancer cells, become ineffective in lung cancers. Researchers from the Icahn School of Medicine at Mount Sinai show that the immune-system molecule TREM2, expressed on macrophages, inhibits the number and efficacy of natural killer cells. This discovery suggests that targeting TREM2 macrophages may represent a potential new strategy for enhancing NK cell activity. The research was published in Nature Immunology.
Previous research has shown that many tumors from patients with non-small-cell lung cancer—the most common type, accounting for 85% of all lung cancers—and other cancers are deprived of natural killer cells. In recent years, experts have made significant progress in understanding how tumors evade these cells when they are present. However, it remains unclear why NK cells are often depleted in cancer.
In the current study, macrophages, another type of immune cell, were identified as the culprit. During tumor progression, the researchers found that bone marrow macrophages act to suppress the recruitment and activation of natural killer cells. The team found that in human lung tissue, the number of NK cells was inversely correlated with those of immune system macrophages—particularly those expressing TREM2. In the presence of a tumor, macrophages trigger a pro-tumorigenic program by triggering TREM2 expression.
Next, the team studied what happened when TREM2 was inhibited in two separate approaches. First, they blocked TREM2 activity using an antibody in mouse models. Next, they studied genetically deleted Trem2 in knockout mice. In both mouse models, TREM2 inhibition significantly reduced lung tumor growth.
“What we saw is that knocking down the TREM2 macrophages resulted in the accumulation of NK cells—they boosted the number of NK cells,” said Miriam Merad, MD, PhD, senior author of the study. “That was important for us because NK cells are always extremely reduced in tumor lesions, and we know they are a big part of tumor surveillance. These results told us that maybe those TREM2-expressing macrophages get rid of NK cells so the tumor can progress.”
In the last part of the study, the team studied the synergistic effects of NK-activating agents, in this case an antibody, to boost an antitumor response. Treatment resulted in a strong reduction of tumor growth in wild type mice.
“These results support the strategy of developing combination therapies that concurrently block TREM2 macrophages and boost natural killer cells as a new way of boosting anti-cancer immunity,” said Merad.
The lab is working on developing human NK cell booster antibodies and anti-TREM2 macrophage antibodies.
“We need to be aware that NK cells have both activating and inhibiting receptors,” says Merad. “For this reason, they can be very dangerous, and we have to be sure that when we boost NK cells we are not killing healthy cells – just those damaged cancer cells.”
Although this work was done in lung cancer, the team believes dual therapy with TREM2 macrophage inhibitors and NK cell boosting agents may have applicability in other cancer types. Currently, Merad’s team has found that TREM2 macrophages are abundant in colorectal and liver cancers.
“It seems that it is a common strategy for tumors to recruit TREM2 macrophages to help them grow because they destroy NK cells and enable those tumors to progress,” said Merad.
