Researchers Develop Macrophage ‘Backpacks’ to Combat Tumors in Mice

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering and the John A. Paulson School of Engineering and Applied Sciences (SEAS) published a study on Wednesday in Science Advances, revealing their development of cytokine-secreting “backpacks” for macrophages. These “backpacks” keep key immune cells in a tumor-killing state for up to five days after they approach a tumor.

Macrophages can defend against pathogens in the body, aid in wound healing and regulate tissue homeostasis. They rely on soluble cues in the tissue environment to direct their polarization into various phenotypes. For this reason, they may be able to be harnessed for the development of anticancer immunotherapies. In initial tests conducted by the researchers, the macrophages appeared to slow tumor growth and reduce metastasis in mice with an aggressive form of breast cancer.

“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,” study author C. Wyatt Shields, PhD, told Genetic Engineering and Biotechnology News. “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 “backpacks” are made of two layers of biocompatible polymer poly (lactic-co-glycolic) acid (PLGA), with polyvinyl alcohol (PVA) and the cytokine interferon gamma (IFNγ) in between them. IFNγ is a known potent stimulator of the proinflammatory response in macrophages, and it has shown that it can reduce the size of some tumors. Shields and his colleagues mixed macrophages with their backpack particles in vitro, and discovered that approximately 87% of the cells picked up one to four “backpacks” on their surfaces. They remained there for at least five days during the study without being consumed. Afterward, the “backpacks” were able to give off IFNγ for at least 60 hours.

The researchers also tested macrophages for various markers that indicated whether they were in a proinflammatory (M1) state that fights tumors, or an anti-inflammatory state (M2). The macrophages that carried the “backpacks” expressed three M1-related factors more strongly, compared to blank “backpacks” or macrophages in the presence of free IFNγ.

The team also tested the “backpacks” by injecting them directly into tumors in mice to see if they could maintain their M1 state. In the end, the macrophages with the “backpacks” expressed M1 indicators for at least 48 hours.

Detailed analysis showed that the macrophages with “backpacks” not only remained in their M1 state, but helped other tumor-related macrophages revert from an M2 state back to an M1 state.

“Macrophages can make up roughly 50% of the mass of a tumor,” Shields continued. “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.”

Earlier this month, scientists at Purdue University developed a new therapy option that could also potentially halt tumor growth, specifically in patients with prostate cancer. Using a protein called interleukin-27, the researchers were able to reduce tumor growth and stop cancer from spreading elsewhere within the body.

“Immune cells are naturally attracted to areas of the body with lots of signals that come from proteins such as IL-27,” said Marxa Figueiredo, associate professor of basic medical sciences in Purdue’s College of Veterinary Medicine, who led the research. “So, with our novel approach of targeting the IL-27 to the tumor or bone cells, we can use these proteins to produce signals that bring healthy cells to areas of the body with cancer or other disease and kill the tumors and begin the process of repairing bone and other musculoskeletal tissues.”

The research team, along with the Purdue Research Foundation Office of Technology Commercialization, are still looking for partners for this new cancer therapy.