mammary gland
The mammary gland is a dynamic organ that undergoes dramatic remodelling throughout life. The branching ducts bloom to form milk-producing 'factories' in lactation, which must be eliminated once lactation stops as part of a process called involution. [Dr Caleb Dawson, Walter and Eliza Hall Institute]

Breast cancer researchers in Australia have discovered a new type of immune cell in breast tissue that helps to keep mammary ducts healthy. Using advanced three-dimensional imaging techniques, the scientists, headed by a team at the Walter and Eliza Hall Institute of Medical Research, discovered that these ductal macrophages (DMs) monitor for threats in the mouse mammary ducts and help to maintain tissue health by clearing away dying milk-producing cells once lactation stops. As well as being the sites where milk is produced and transported, mammary ducts are also where most breast cancers arise.

The authors suggest that understanding how these immune cells function could provide valuable insights into potential new approaches to treating breast cancer. “We discovered an entirely new population of specialized immune cells, which we named ductal macrophages, squeezed in between two layers of the mammary duct wall,” said Caleb Dawson, PhD, co-senior and first author of the team’s paper, which is published in Nature Cell Biology, in a report titled, “Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodeling.”

Dawson’s colleagues on the research included Walter and Eliza Hall Institute scientists Geoff Lindeman, PhD, Jane Visvader, PhD, along with Anne Rios, PhD, who is now based at the Princess Máxima Center for Pediatric Oncology, in the Netherlands.

The mammary gland is a dynamic organ that undergoes dramatic remodeling throughout life, the authors explained. The branching ducts bloom to form milk-producing alveoli during lactation, which must then be eliminated once milk production stops. Mammary ducts are of particular interest to breast cancer researchers because this site is prone to cancer development.

Most organs in the body including the brain, liver, lung, skin, and intestine have their own population of macrophages, immune cells that play important roles in regulating infection, inflammation, and organ function within their sites of residence. But while macrophages in breast tissue have been implicated in mammary gland function, “their diversity has not been fully addressed,” the investigators continued.

Using techniques including high-resolution three-dimensional imaging and flow cytometry, Dawson and colleagues discovered a type of ductal macrophage that hadn’t previously been identified. The cells exhibited a distinct gene expression profile that implied a phagocytic function, and proliferated during pregnancy and lactation. “DMs were highly enriched for lysosomal genes, which is indicative of a phagocytic role,” they wrote. “Although DMs were rare in adult mammary glands (0.64% of total cells), they expanded 40-fold during pregnancy and constituted 25.7% of total cells in lactation.”

Further investigation suggested that the DMs phagocytose the alveolar cells during early involution. “We were excited to find that these cells play an essential role at a pivotal point in mammary gland function called involution when lactation stops, milk-producing cells die, and breast tissue needs to remodel back to its original state,” Dawson said. “We watched incredulously as the star-shaped ductal macrophages probed with their arms and ate away at dying cells. The clearing action performed by ductal macrophages helps redundant milk-producing structures to collapse, allowing them to successfully return to a resting state.

Immune cells called macrophages (“big eaters”) are important for mammary gland formation and function. This is a movie of a mammary gland duct (purple), surrounded by collagen fibers (pink) and macrophage populations (yellow and blue). The yellow macrophages are breast-specific ductal macrophages (DMs) that live on the ducts and survey the epithelium with their arms. [Caleb Dawson, PhD, Walter and Eliza Hall Institute of Medical Research]

Interestingly, when the researchers then removed ductal macrophages from mammary ducts they discovered that no other immune cells were able to adequately take over this essential process. “One of the key functions of DMs is to rapidly clear alveolar cells during involution to return the mammary gland to its pre-pregnant state … The lack of replacement of DMs in the alveoli indicates an important phagocytic role that other immune populations are unable to fulfill,” the team noted.

According to Visvader, the discovery of these mammary duct-specific macrophages represents a remarkable step forward in understanding how the immune system interacted with the ductal network and impacted upon mammary gland development. “As breast cancer researchers, there is a need to understand which cells are doing what, so that we can identify how these intricate cellular processes become dysregulated, such as in the case of breast cancers,” she said.

Breast cancer is the most common form of cancer in Australian women, and more than 19,000 Australians are diagnosed with breast cancer every year. Dawson said that going forward, the team hopes to explore the function of ductal macrophages at different stages of mammary gland development, such as the transitions into adulthood and pregnancy, and to try to find out whether this cell type may play a role in cancer development. “Their central role in involution together with their molecular signature in lactation implies an immunosuppressive role,” the investigators noted.

Caleb Dawson, PhD, from the Walter and Eliza Hall Institute, was part of an Australian research team that discovered a new type of immune cell in breast ducts. [Walter and Eliza Hall Institute]

“We also want to investigate the role that these duct-specific immune cells play in helping cancer to grow and spread,” Dawson noted. “Ductal macrophages are spread throughout the mammary ducts. As cancer grows, these macrophages also increase in number. We suspect that there’s the potential for ductal macrophages to inadvertently dampen the body’s immune response, which would have dangerous implications for the growth and spread of cancer in these already prone sites.”

Interestingly, ductal macrophages strongly resemble mammary tumor macrophages and form a network that pervades the tumor, the authors continued. “Thus, the mammary epithelium programs specialized resident macrophages in both physiological and tumorigenic contexts,” the scientists commented. “Indeed, DM-like TAMs [tumor-associated macrophages] can suppress cytotoxic T-cell activity and promote tumor progression, raising inhibition of DM function as a possible preventive therapy for breast cancer.”

Visvader said the team’s ultimate goal was to understand these cells enough to potentially manipulate them. “Given that tumor macrophages likely promote growth of the tumor, blocking their activity could serve as a treatment strategy for breast cancer,” she said.

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