Role finally identified for subset of white blood cells in cancer metastasis.


The primary role of monocytes is to sense the environment and replenish the pool of tissue macrophages and dendritic cells. Recent advances in immunology research have discovered that monocytes can be divided into three subsets based on specific surface markers and their specific functions, namely classical, non-classical or patrolling, and separate murine classifications.  It has been widely accepted that cancer progression is an inherently proinflammatory process and that during tumorigenesis, monocytes will give an anti-tumor response and act both as cells presenting tumour-associated antigens to tumour-infiltrating lymphocytes and as cytotoxic effector cells.

Research has shown that classical monocytes promote tumorigenesis and cancer metastasis, however, how nonclassical or patrolling monocytes interact with tumours is unknown. Now, a study from researchers led by the La Jolla Institute shows that patrolling monocytes may play an anti-cancer role, particularly in the lung.  The team state that their’s is the first study to show that patrolling monocytes directly block lung metastasis, findings that could suggest future immunotherapies to treat an extraordinarily lethal cancer.  The study is published in the journal Science.

Previous studies show that patrolling monocytes cruise the bloodstream, cart off cellular debris, and block invasion of a less benign population of inflammatory cells.  It is well known that these white blood cell scavengers played a beneficial role in counteracting inflammation in the context of atherosclerosis, however, it was unclear what role these specific monocytes played in the formation and spread of cancer.

Earlier studies from the lab discovered that mice lacking a gene called Nr4a1 was required for monocyte survival. The Nr4a1 ‘knockout’ mice specifically lacked patrolling monocytes. At the time no one had looked at how these cells might function in cancer with the knockout mouse providing the model to test this hypothesis.  The current study shows that this subgroup of white blood cell is a key player in orchestrating the killing of metastasizing tumour cells.  These cells recognize and could help destroy early metastasizing tumor cells in the blood, even before they can invade new tissues and form new tumours.

The current study used a mouse-melanoma model with the Nr4a1 gene knockedout and a control group with the Nr4a1 gene present, following where tumour cells migrated via fluorescent tags. Data findings show that within 24 hours, blood vessels in lungs of knockout mice contained more melanoma cells than the control mice, suggesting that the absence of patrolling monocytes made animals vulnerable to lung metastasis.  Patrolling monocytes from normal mice were then transfused into the bloodstream of knockout mice before injecting tumour cells. Data findings show that this inhibited cancer cell migration into lung vasculature, suggesting that these cells can be added ‘back’ into a mouse that lacks them to reduce metastasis.

Results show that when researchers transfused patrolling monocytes into mice after cancer cells were injected, metastasis still occured. The researchers explain this may mean that patrolling monocytes are required to halt a metastatic cell, in other words; patrolling monocytes had to be in place in the bloodstream before the invaders arrived to keep them from breaching the vessel wall.  To validate this this finding the group made real-time videos of the fluorescently labeled cancer cells and patrolling monocytes in vessels of living mice. In them, glowing green monocytes race after red-tagged cancer cells and were observed physically blocking the cancer cells from gaining a foothold in vessel walls, where they could access lung tissue if unimpeded.

The team state that they didn’t observe patrolling monocytes directly kill tumor cells, noting that the patrollers appear to engulf debris from tumour cells, with it remaining unclear whether the patrolling monocytes administer the death blow.  However, the lab go on to add that what is certain is that the patrolling monocytes recruit other immune cells called natural killer cells that are capable of killing tumour cells.  The researchers note that it has recently been hypothesized that one way in which tumours spread is by lobbing microvesicles at neighbours. The group conclude, therefore, to undermine a metastatic cell all a patrolling monocyte may need to do is tidy up after it.

The team surmise that their study shows effects primarily in lung because there are a lot of these types of monocytes normally present in that tissue.  They go on to add that patrolling monocytes may prevent metastasis to other organs as well.  For the future, the researchers state they now plan to augment existing immunotherapy approaches to prevent tumour metastasis by identifying reagents to increase the number or activity of patrolling monocytes, either as pharmaceuticals or possibly by transferring cells into a patient.

Source: La Jolla Institute for Allergy and Immunology

 

Tumor material uptake by patrolling monocytes. Imaging of A549 human lung carcinoma material uptake by CD14 dim CD16+ human monocytes after 24 hrs of co-culture. Monocytes are labeled with CD16 (blue) and tumor/tumor material is labeled with CellTracker Green (arrows mark monocyte uptake of tumor, high magnification image of representative monocyte in upper right corner). Patrolling monocytes control tumor metastasis to the lung. Hedrick et al 2015.

Tumor material uptake by patrolling monocytes. Imaging of A549 human lung carcinoma material uptake by CD14 dim CD16+ human monocytes after 24 hrs of co-culture. Monocytes are labeled with CD16 (blue) and tumor/tumor material is labeled with CellTracker Green (arrows mark monocyte uptake of tumor, high magnification image of representative monocyte in upper right corner). Patrolling monocytes control tumor metastasis to the lung. Hedrick et al 2015.

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