“Backpacks” for key immune cells hold them in a cancer-killing state

The human body has a variety of weapons it can deploy to fight off cancer, but being the crafty foe that it is, the disease has plenty of evasive tactics it can use to survive and thrive. Scientists at Harvard have come up with a new way to supercharge immune cells that are one of our key defenses against cancerous cells, equipping them with a type of “backpack” that served to slow tumor growth in mice.

The focal point of the Harvard research is a type of immune cell called a macrophage, which can play an important role in searching for and destroying threats like cancer while operating in a pro-inflammatory state known as M1.

But macrophages can also be recruited to support the cause of the cancer cells, which can flip a switch that makes them suppress the body’s immune response, promote blood flow to the tumor and help it metastasize, or spread. This anti-inflammatory state is known as M2.

Preserving macrophages in their tumor-killing M1 state is therefore a key objective for cancer researchers, though this has proven difficult with cancer cells overcoming most efforts so far, maintaining the ability to switch them into the M2 pro-tumor state. The Harvard team has spent the better part of a decade investigating how specially designed “backpacks” could swing things back in our favor, and have now made a significant breakthrough.

These backpacks consist of layers of biocompatible polymers, with polyvinyl alcohol and a special type of cytokine called IFNγ sandwiched in between. This cytokine has proven to be a powerful stimulant of pro-inflammatory behavior in macrophages and is capable of reducing some tumors in size. The hope was that by integrating it into these backpacks, the cytokine could be slowly secreted and keep the macrophages in the desired M2 state for longer.

Backpacks attached to a macrophage cell, as seen in pink
Backpacks attached to a macrophage cell, as seen in pink

Wyss Institute at Harvard University

These disc-shaped backpack particles were mixed with macrophages in vitro, where most of the immune cells naturally loaded themselves up with these new pieces of luggage. Testing showed that these macrophages exhibited much stronger traits indicative of an M1 state than the other macrophages used in the experiments.

The next round of experiments involved mice with aggressive forms of metastatic breast cancer. The researchers injected the backpack-toting macrophages into the tumors and assessed them one week later, with pleasing results. The team found indicators of the M1 tumor-killing state for a period of at least 48 hours, while the mice treated with this technique had “significantly” fewer metastatic nodules and smaller tumors than the control group.

Further investigations revealed that the backpacks were not only helping hold those macrophages in an M1 state for longer, they actually saved other macrophages from that had been recruited by the tumor. These tumor-associated macrophages could actually be returned from their M2 state to an M1 state, and rejoin the fight with their new comrades.

“Macrophages can make up roughly 50 percent of the mass of a tumor,” says first author of the study C. Wyatt Shields. “If we are able to switch them into their M1 state and sustain that activation, it could massively reduce the size of tumors and give both the immune system and treatments like chemotherapy better access to the cancer cells themselves.”

In addition to treating cancer, the researchers believe these backpacks also hold potential for treating a host of diseases that can be brought on by unwanted inflammation, such as rheumatoid arthritis, Crohn’s disease, and lupus. If the backpacks can be loaded with different agents as a way of reversing the effects so that the macrophages shift from a pro- to an anti-inflammation state they could temper inflammation rather than promote it.

“This study speaks to the beauty of macrophages – they are highly adaptable cells that respond very strongly to stimuli in their environment, but this can also be a problem when they receive a stimulus that tells them to do something that’s actually harmful to the body, like helping cancer grow or metastasize,” says Shields. “We have shown that it’s possible to provide a sustained stimulus via these backpack particles to keep macrophages in their desired state, and we hope that this technique could one day be used to treat a variety of conditions related to immune dysfunction.”

The team will now continue developing the backpacks to explore these possibilities, and have published their research in the journal Science Advances.

Source: Harvard University

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