Normally, a class of immune cells known as macrophages patrol the body and engulf cellular waste, foreign organisms and other substances that pose threats. But tumors have a way to switch macrophages into a different state that instead promotes the survival and growth of the cancer.
A team of scientists at Harvard University has found a way to turn macrophages back to their cancer-killing state by attaching to their surfaces little “backpacks” that produce stimulatory cytokines. In a mouse model of breast cancer known to have a highly immunosuppressive environment, the engineered macrophages showed durable anti-tumor effects, according to research published in the journal Science Advances.
Even though macrophages have a reputation for being nonspecific defenders against anything they recognize as foreign to the body, they can can carry around small disc-shaped particles for days without gobbling them up, a research team led by Harvard bioengineer Samir Mitragotri, Ph.D., previously found. Mitragotri, the new study’s co-author, and colleagues figured they could keep macrophages in a cancer-fighting state with a little help from interferon gamma, which is known for its anti-tumor activity.
His team designed backpacks carrying interferon gamma. In lab dishes, the researchers found that about 87% of the macrophages picked up one to four backpacks on their surfaces and that the backpacks kept secreting interferon gamma for at least 60 hours.
Macrophages rely on various cues from the tissue microenvironment to switch between two states. In the M1 state, they produce cytokines to launch an immune response, while the M2 state is linked to healing and tissue regeneration. In cancer, macrophages typically stay in the M2 state due to the immunosuppressive microenvironment of tumors. That promotes tumor formation, metastasis and chemo resistance.
The Harvard scientists showed that macrophages carrying interferon gamma strongly exhibited signs of M1, with expression of some immune biomarkers reaching much higher levels than what was seen in macrophages carrying blank backpacks or those that were in the presence of free interferon gamma.
To evaluate the therapeutic efficacy of the backpack-bearing macrophages, the researchers administered them to mice with an aggressive form of metastatic breast cancer. They found that the rodents had significantly fewer metastatic nodules and smaller tumors than did control mice, and they lived longer. What’s more, not only did the macrophages with the engineered backpacks maintain their M1 state, they also shifted macrophages in the tumors toward that anti-cancer state.
Particle-based immune cell therapies have been studied before in cancer. In 2018, scientists at the Massachusetts Institute of Technology used cytokine IL-15 backpacks to boost the anti-tumor activity of CAR-T and TCR-T cells.
Macrophages are also being explored as cancer immunotherapy by other research groups. Scientists at the University of Pennsylvania recent attached tumor antigen-specific CARs to macrophages in the hopes of overcoming several shortcomings of CAR-T cells. The technology is being developed by Carisma Therapeutics, a Penn spinout with financial backing from AbbVie.
The Harvard team argues that the new backpack technology can overcome a major hurdle that has impeded efforts to turn macrophages into cancer immunotherapy, namely their tendency to shift to a pro-tumor state. “Macrophages can make up roughly 50% of the mass of a tumor. 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,” said first author C. Wyatt Shields, Ph.D., an assistant professor at the University of Colorado Boulder who completed the study as a postdoctoral fellow at Harvard, in a statement.