Unlike classic monocytes, which can exacerbate metastasis upon recruitment to tumor sites, patrolling monocytes play a preemptive anticancer role by engulfing tumor cells and slowing their spread, particularly to the lung.
A specialized type of white blood cell that helps defend the body from infection also appears to control the spread of cancer. Researchers have found that these innate immune cells, called patrolling monocytes (PMo), slow tumor metastasis to the lung in multiple mouse models (Science 2015;350:985–90).
Most of the body's monocytes are the classic variety, which gobble up bacteria, viruses, and dying cells when recruited to sites of infection. Approximately 10% to 25% are PMo—active surveyors that can travel against blood flow to clear pathogens and other unwanted cells. In the context of cancer, the team discovered that PMo can “sense tumor cells, move toward them, help orchestrate their killing, and clear the tumor cells' debris before they metastasize,” says senior author Catherine Hedrick, PhD, of the La Jolla Institute for Allergy and Immunology in La Jolla, CA.
Hedrick and lead author Richard Hanna, PhD, had long investigated the role of monocytes in atherosclerosis, but shifted their focus to cancer after research from Jeffrey Pollard, PhD, director of the MRC Center for Reproductive Health at the University of Edinburgh, United Kingdom, suggested that classic monocytes promote tumor growth and metastasis (Nature 2011;475:222–5). Meanwhile, others had shown that PMo could clear damaged endothelial cells, and Hanna observed a striking enrichment of PMo in the lung—a common site of metastasis (Cell 2013;153:362–75). This got him wondering if PMo might play a clean-up role in cancer, perhaps helping remove tumor cells within the lung.
Hanna, Hedrick, and their team tested this idea in three mouse models. First, they injected mice with lung carcinoma cells and saw that PMo swarmed to tumor sites, preventing tumor cells from attaching to lung blood vessels. Next, the researchers injected melanoma cells into PMo-deficient mice, which developed lung metastases earlier and in greater numbers compared to control mice.
A third line of evidence for PMo's role in preventing metastasis came from experiments with mice that spontaneously develop breast tumors that spread to the lung. When the immune system in these animals was replaced with that of PMo-deficient mice, the number of spontaneous lung metastases rose dramatically, suggesting that PMo guard against metastasis. This was confirmed with “rescue” experiments where, prior to tumor injection, PMo were reconstituted in mice that lacked these immune cells; in this setting, very few lung metastases formed.
The researchers suspect CX3CL1 (fractalkine) is important for drawing PMo to the lung. This protein is highly expressed in lung epithelial and tumor cells, and its receptor, CX3CR1, is abundant on the surface of monocytes. In the lung, it's hard to tell if PMo are directly killing tumor cells. But “we know they orchestrate it,” says Hedrick. “They make a lot of the chemokines that recruit natural killer cells,” which are known for their ability to kill tumor cells.
All told, the new research suggests there is a balance of protumor and antitumor activities within the innate immune system, says Pollard, who wasn't involved with this study. “From a therapeutic point of view, enhancing patrolling monocytes might help tilt the balance toward an antimetastatic role.” –Esther Landhuis
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