Neutrophils, the most abundant white blood cells in humans, help tissues heal in response to injury, but this tissue repair may also help tumor cells to form metastases in radiation-injured lungs, according to a new study in mice.
“These authors conducted a rigorous series of experiments, identifying the infiltrating neutrophils as being primarily responsible for priming the lungs to grow metastases,” Michael MacManus, a radiation oncologist at Peter MacCallum Cancer Centre in Australia who was not involved in the study, tells The Scientist in an email. “These results are of very significant interest, at least with respect to the understanding of metastasis of murine models where entire lungs can be irradiated with relatively large fractions of radiation.”
In a previous study, the researchers found that metastatic cancer cells induced a tissue regenerative program in the lining of the lungs, known as the epithelium. In the new work, published February 24 in Nature Cancer, the team explored the implications of that program, coauthor Ilaria Malanchi, a cancer biologist at the Francis Crick Institute in London, tells The Scientist: “Does that mean that, if the tissue is in a regenerative status for another reason, it provides a better environment for tumor cells?”
Neutrophils modify the tissue to support healing, but by doing that, unintentionally help the tumor cells to grow.—Ilaria Malanchi, the Francis Crick Institute
To find out, Malanchi and her colleagues injured healthy mouse lungs by irradiating the thorax. When the researchers injected breast cancer cells into the mice’s tails or fat pads after radiation, metastases grew more readily in irradiated lungs than in the non-irradiated lungs of control animals. When looking for a likely culprit for this difference, the researchers found histologically that the irradiated lungs were infiltrated by neutrophils, a type of immune cell that promotes inflammation and fights infections. When the researchers depleted neutrophils from the mice using an antibody, metastases did not form.
In a next experiment, the researchers transferred radiation-primed neutrophils into the lungs of non-irradiated mice, and found that these neutrophils promoted the formation of metastases by influencing the tissue around them, particularly the lung epithelium. In lung epithelial cells, neutrophils enhanced stem cell signaling, including the Notch pathway, as indicated by changes in transcription. Notch signaling, a regulator of stem cell proliferation and differentiation during tissue repair, was also enhanced within the metastatic niche, the local microenvironment where metastases develop, and in metastatic cancer cells, as shown by single-cell RNA sequencing and immunostaining of HES1, a Notch target gene.
To test how this increased Notch signaling affects metastatic cells, the researchers grew cancer cells in ex vivo conditions. “If . . . we test them for their tumorigenicity ex vivo, so their ability to initiate new growth in challenging condition, they were much better if they have been exposed to the previously irradiated lung, really proving an increased in tumorigenicity,” Malanchi summarizes in an email to The Scientist. “Activation of regenerative pathways in the tissue—in this case Notch—feeds into the tumor cells’s potential to grow and leads to an increase in metastasis.” Neutrophil activation after injury is therefore a double-edged sword, according to Malanchi. “Neutrophils modify the tissue to support healing, but by doing that, unintentionally help the tumor cells to grow.”
The study “is one more very well designed paper providing evidence for the importance of neutrophils, putting neutrophils at the center as a major determinant for disease pathophysiology,” Ioannis Kourtzelis, an immunologist at the University of York in the UK who was not involved in the study, tells The Scientist. Neutrophils have also been implicated in autoimmunity, chronic inflammation, sepsis, and others.
Malanchi is careful to highlight that the broad tissue injury that was intentionally induced in this study is unlikely to be seen in patients. “Radiation therapy right now is very focused on the tumor,” and exposure of healthy tissue is limited, she says.
MacManus also points out that similar phenomena are rarely observed in patients. “Lung irradiation is an inevitable consequence of many modern human treatment regimens for cancers around the thoracic cavity,” he says, but “There is at present very little evidence in the literature to suggest that radiation-supported lung metastasis might be an important phenomenon in humans with cancer.”
Clinically, it’s more probable that cancer cells would disseminate to lung tissue before rather than after the area is exposed to radiation in the course of treatment, Olivier De Wever, a cancer research at Ghent University, Belgium, who was not involved in the study, tells The Scientist in an email. “It would have been interesting if the preclinical model included a lung radiation protocol following the presence of disseminated cancer cells,” De Wever writes. “Would a similar acceleration of lung colonization be observed? The presence of disseminated cancer cells in the lungs may induce a tumor microenvironment that differently reacts to irradiation compared to the normal lung environment.”
However, neutrophils might still play a role in cancer’s spread in patients, Malanchi adds. “The question is, are neutrophils doing this in a normal situation, without having an injured tissue. Do neutrophils—at the early stage—also support the loop between the regenerative niche and the cancer cell?” If so, she says, “Then you can at least target that cell and somehow reduce this feed-forward loop.”