Neutrophils, the workhorses of the immune system, are the most abundant type of white blood cell in the human body. Samir Mitragotri, a biomedical engineer at Harvard University, sought to leverage the versatility of neutrophils, in particular, their ability to finetune inflammation, to develop strategies that harness the body's own immune system to combat tumors.
In a new study, Mitragotri, used disc-shaped microparticles, dubbed "backpacks," to activate neutrophils and enhance their anti-tumor properties (1). This approach, reported in Nature Biomedical Engineering, may serve as a new tool for immunotherapy in the future.
Currently, researchers use neutrophils to bolster the immune systems of people with cancer who are undergoing chemotherapy. However, directly harnessing neutrophils to target cancer itself has remained largely unexplored territory.
“Neutrophils have always fascinated me, and they are the largest part of white blood cells, but they are not used for any cell therapy,” said Mitragotri. “Neutrophils get activated when they bind to a surface. We thought, can we use backpacks as a surface to activate neutrophils?”
Neutrophils have always fascinated me, and they are the largest part of white blood cells, but they are not used for any cell therapy.
-Samir Mitragotri, Harvard University
Mitragotri previously developed backpacks to influence the behavior of a different immune cell population, macrophages, by prompting them to fight cancer and multiple sclerosis in animal models (2). Building on these findings, Mitragotri hypothesized that the backpack approach could be adaptable to neutrophils as well.
When neutrophils encounter a foreign object too large to engulf, such as a splinter or surgical implant, they polarize to a phenotype that can alert the immune system (3). The key for the researchers was to design backpacks large enough to trigger this response but small enough not to impede neutrophil movement and function.
Their solution involved crafting a new type of backpack with an optimized smaller size termed Cyto-Adhesive Micro-Patches (CAMP). The CAMP were modified with the antigen-binding fragment of anti-CD11b antibody, chosen for its high expression on the neutrophil surface and role in adhesion during the leucocyte recruitment cascade. These new backpacks were smaller, able to evade neutrophil engulfment, and devoid of any immune-stimulatory molecules traditionally used to activate immune cells.
“What we are looking at is a system that can stay on the surface and provide the cell with the right stimulation,” Mitragotri commented. “That's where backpacks really stand out. They are large enough to make the cell essentially think that it's a substrate. It can attach to it, grow on it, and get the right kind of support. At the same time, it is small enough so that it can take it wherever it goes. That's what's unique about this approach.”
In their experiments, the researchers observed that CAMP readily adhered to freshly isolated mouse neutrophils without causing cell death. Gene expression analysis revealed that CAMP treatment significantly altered the activity of more than 4,000 genes in neutrophils, with a specific upregulation of genes associated with the anti-tumor state and anti-inflammatory cytokines. Co-culturing these CAMP-armed neutrophils with other immune cells, including T cells, natural killer (NK) cells, dendritic cells, and macrophages, revealed an additional benefit: the neutrophils activated these partner cells as well.
The ultimate test, however, was to determine if CAMP could maintain neutrophil activation within the immunosuppressive environment of a tumor. The group injected CAMP-bearing neutrophils into mice with melanoma. The researchers then imaged the mice to confirm neutrophil migration to the tumor site within just four hours. They observed high numbers of neutrophils in the spleens and tumor-draining lymph nodes of these mice, along with activated CD8+ T cells and NK cells, indicating proper immune infiltration.
The group further examined the effect on tumor growth. Mice with melanoma treated with CAMP-loaded neutrophils displayed significantly slower tumor growth rates. In a breast cancer model, the treatment resulted in prolonged survival, with complete tumor regression observed in 15 percent of the animals.
The researchers then explored the potential synergy between their neutrophil therapy and a standard checkpoint inhibitor drug for cancer. The combination treatment in mice with melanoma yielded significantly reduced tumor growth and improved overall survival rates within 60 days. These mice displayed a robust anti-tumor memory response and completely resisted the development of new tumors upon re-challenge.
Joerg Lahann, a biomedical engineer at the University of Michigan who was not a part of this study said, “We are moving through multiple eras of cancer therapy. We were already in the middle of cell-based therapies. Now it’s just the beginning of getting into this era. This is really a kind of pioneering and could be a real breakthrough.”
The use of CAMP offers a unique strategy to activate neutrophils and enhance their anti-tumor properties. The encouraging nonclinical data demonstrating not only tumor growth suppression, but also robust anti-tumor memory underscores the promising future of this technology. Further research should optimize the lifespan of CAMP-activated neutrophils and assess their efficacy against a broader range of cancers. However, this work paves the way for the development of a novel and potentially transformative neutrophil-based immunotherapy for cancer patients.
“By being able to control the immune cells, I think there is tremendous potential to control the outcome of the disease,” Mitragotri concluded.
References
- Kumbhojkar, N. et al. Neutrophils bearing adhesive polymer micropatches as a drug-free cancer immunotherapy.Nat Biomed Eng 1, 1–14 (2024).
- Shields, C. W. et al. Cellular backpacks for macrophage immunotherapy.Science Advances 6, 65-79 (2020).
- Herrero-Cervera, A., Soehnlein, O. & Kenne, E. Neutrophils in chronic inflammatory diseases.Cell Mol Immunol 19, 177–191 (2022).