Certain immune cells apparently play a dual role in the fight against cancer: so-called neutrophilic granulocytes were previously known primarily for promoting tumor growth. However, a study now shows that under certain conditions they can also be effective weapons against cancer. They play a crucial role in whether an immunotherapy against cancer is successful or fails. The findings could help to develop more targeted and effective immunotherapies in the future.
Immunotherapies against cancer increase the ability of immune cells to recognize and eliminate abnormal cells. They primarily target the T cells, which are part of the adaptive immune system. For some types of cancer, including malignant melanoma and lung cancer, such therapies can mean the decisive step on the way to healing for some patients. In many cases, however, immunotherapy does not bring about the desired success. It is still largely unclear why immunotherapies work in some patients and fail in others.
Innate immune system supports cancer defense
A team led by Jeremy Gungabeesoon from Harvard Medical School in Boston has now identified an important factor that contributes to the success or failure of immunotherapy. “To develop advanced treatments that turn immunotherapies into a real therapeutic revolution, it is important to decipher the immune components involved,” says Gungabeesoon’s colleague Mikael Pittet. The team focused on the so-called neutrophilic granulocytes. These are part of the innate immune system and make up most of the immune cells in the blood. In the event of infections and injuries, they quickly release antimicrobial factors and are therefore among the first to fight pathogens. However, in the context of cancer, it has been shown that they can promote vascularization and tumor growth.
To better understand the role of neutrophils in cancer, the team administered immunotherapy to mice with lung cancer. In animals whose tumors responded well to treatment, the researchers found that the number of neutrophils in the lungs had more than doubled two days after treatment. “This initial result contradicted what was known about the role of neutrophils in cancer,” explains Gungabeesoon’s colleague Allon Klein. “That prompted us to go further to understand the reasons.”
Neutrophils more diverse than thought
In a series of other experiments, the team found that neutrophils are more diverse than previously thought. “Those that we observe in response to immunotherapies are very different from those that are discovered in progressive tumors and carry different markers,” reports Klein. The transcription factor IRF1, which reacts to the inflammatory messenger interferon, apparently plays an important role here. If the researchers suppressed IRF1 in the neutrophils of the mice, this led to the failure of the immunotherapy.
In addition, Gungabeesoon and his team evaluated data from a small clinical study on immunotherapy in human patients with lung cancer. Here, too, it was shown that patients with a strong neutrophil response had a better course of the disease and survived more often. “These results suggest that a therapy-induced systemic neutrophilic response may positively correlate with disease progression in lung cancer patients,” the team concludes. However, only data from 78 patients were included in the study, so that the meaningfulness is limited so far.
Combination therapy for double immune attack?
In future studies, the team wants to further investigate the role of neutrophils in cancer. “It seems that the fate of the neutrophils, which act for or against a tumor, is already determined during their formation in the bone marrow,” explains Mikael Pittet. “Would it then be possible to manipulate them in the fight against tumors? That’s what we want to explore now.” The results so far suggest that neutrophils might be able to eliminate cancer cells that are hiding from the T cells. “Hence, cancer immunotherapies that induce anti-tumor T-cell immunity in combination with therapies that optimally target anti-tumor neutrophils could result in more durable tumor control after treatment,” the researchers said.
Source: Jeremy Gungabeesoon (Harvard Medical School, Boston, Massachusetts, USA) et al., Cell, doi: 10.1016/j.cell.2023.23.032