For many patients, they produce remarkable results. For others, they do nothing.

We still don’t really know why. But in new research published in the Journal of Experimental Medicine, we observed immune cells called macrophages attacking melanoma cells in real time – which may offer clues about how we can make those therapies work for all patients, not just some.

Tumours, hot and cold

One of us (Yuki) treated patients with melanoma in Japan as a dermatologist. The other (Tri Phan) runs a lab at the Garvan Institute in Sydney, where his team specialises in observing the cells of the immune system in real time.

When Yuki wanted to understand why immune checkpoint inhibitors were failing for many patients, she joined Tri Phan’s lab to continue her research.

The treatment fails in what oncologists call “cold” tumours, where the cancer’s environment actively prevents a kind of immune cell called a T cell attacking it. One of our lab’s aims is trying to work out how to make the tumours “hot”, allowing T cells to penetrate and destroy the cancer cells.

Our new findings suggest a different kind of immune cell, called macrophages, may hold the key.

The housekeepers we’ve been ignoring

In 1908, Russian zoologist Ilya Mechnikov was awarded a Nobel Prize for the discovery of phagocytosis (“cell eating”) in the immune system, which is carried out by cells he called macrophages (from the Greek for “big eaters”).

These cells engulf and clear away the debris caused by tissue damage and cell death. They are often regarded as the body’s silent, no-fuss housekeepers.

However, their role in cancer has often been overlooked. Unlike other immune cells that move through the blood and patrol the whole body, macrophages are “tissue-resident” and stay in one place.

Earlier studies of the role of macrophages in cancer assumed these housekeepers were all the same. But when we looked closely in the skin, it became clear that there were many different kinds of macrophages living in different layers.

One particular kind of macrophages (recognised by a protein called CD169) lives in a deeper part of the skin, called the hypodermis.

We found that these macrophages arranged themselves around the edges of a melanoma tumour, as if they were trying to wall it off. When we depleted the macrophages, the melanomas grew bigger, suggesting they were constraining the growth of the tumours.

Watching cancer cells being eaten alive

To understand what these CD169-positive macrophages were actually doing, we used an advanced imaging technique called intravital two-photon microscopy. This allows us to watch biological processes unfold in living tissue in real time.

What we saw was surprising: the macrophages were “nibbling” and actively engulfing live melanoma cells. While we had seen macrophages eat dead cells in our lab before, we had never seen them eat a live melanoma cell in a model organism.

What was even more surprising was that this immune attack was happening without the need for T cells, or antibodies made by another kind of immune cell called B cells – the immune players most commonly credited with fighting cancer.

We also confirmed this is not something that just happens in the lab. Our colleagues at the Melanoma Institute Australia analysed samples from human melanoma patients and found similar populations of CD169-expressing macrophages on the edges of the tumour, suggesting they may play a similar protective role there.

Calling in the cavalry – implications for therapies

Macrophages don’t just clear away debris. They can also alert the immune system to danger. After they have digested the debris, they can display it like a biological “red flag” to direct T cells to find and kill the cancer cells.

What makes a macrophage decide whether to silently dispose of debris without alerting the immune system, or wave the red flags to activate the immune system, is still unclear. Because the CD169-expressing macrophages are strategically positioned around the tumours, we suspect they may hold the key.

Macrophages are widespread in most solid tumours – including glioblastoma, breast cancer and many others. This is an army already in place waiting to be mobilised.

Our next step is to understand precisely how these macrophages eat live cancer cells and how they can communicate the danger to T cells, so we can harness this population with new treatments.

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Billions of cells die in your body every day. Some go out with a bang, others with a whimper.

They can die by accident if they’re injured or infected. Alternatively, should they outlive their natural lifespan or start to fail, they can carefully arrange for a desirable demise, with their remains neatly tidied away.

Originally, scientists thought those were the only two ways an animal cell could die, by accident or by that neat-and-tidy version. But over the past couple of decades, researchers have racked up many more novel cellular death scenarios, some specific to certain cell types or situations. Understanding this panoply of death modes could help scientists save good cells and kill bad ones, leading to treatments for infections, autoimmune diseases, and cancer.

“There’s lots and lots of different flavors here,” says Michael Overholtzer, a cell biologist at Memorial Sloan Kettering Cancer Center in New York. He estimates that there are now more than 20 different names to describe cell death varieties.

Here, Knowable Magazine profiles a handful of classic and new modes by which cells kick the bucket.

Unplanned cell death: Necrosis

Lots of bad things can happen to cells: They get injured or burned, poisoned or starved of oxygen, infected by microbes or otherwise diseased. When a cell dies by accident, it’s called necrosis.

There are several necrosis types, none of them pretty: In the case of gangrene, when cells are starved for blood, cells rot away. In other instances, dying cells liquefy, sometimes turning into yellow goop. Lung cells damaged by tuberculosis turn smushy and white — the technical name for this type, “caseous” necrosis, literally means “cheese-like.”

Any form of death other than necrosis is considered “programmed,” meaning it’s carried out intentionally by the cell because it’s damaged or has outlived its usefulness.

A good, clean death: Apoptosis

The two main categories of programmed cell death are “silent and violent,” says Thirumala-Devi Kanneganti, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. Apoptosis, first named in 1972, is the original silent type: It’s a neat, clean form of cell death that doesn’t wake the immune system.

That’s handy when cells are damaged or have served out their purpose. Apoptosis allows tadpoles to discard tail cells when they become frogs, for example, or human embryos to dispose of the webbing between developing fingers.

The cell shrinks and detaches from its neighbors. Genetic material in the nucleus breaks into pieces that scrunch together, and the nucleus itself fragments. The membrane bubbles and blisters, and the cell disintegrates. Other cells gobble up the bits, keeping the tissue tidy.

The post Your cells are dying. All the time. appeared first on MASSIVE News.