ABOVE: Researchers underscored the importance of macrophage transport properties, which may provide insights for designing more efficacious therapies. © iStock, Dr_Microbe

Macrophages serve as the Swiss army knives of the innate immune system, switching between phenotypes to perform different functions in response to the surrounding environment. One of their key attributes is their mobility to sites of inflammation, infection, and tumors. This trait garnered the attention of researchers who developed therapies to leverage macrophages’ abilities.1 

There are three different macrophage types, naïve (M0), antitumor (M1), and protumor (M2). M1 macrophages accumulate at the tumor and exert antitumor activity. Researchers have attempted to use them in adoptive cell therapies, but these cell therapies are in their early stages with limited clinical success.2 One aspect that may influence treatment efficacy is how the macrophages traffic to the tumor. For now, the dynamics of macrophage movement are poorly understood. 

Samir Mitragotri, a bioengineer at Harvard University, wondered, “If we look at the transport properties of activated M1 macrophages and the naïve M0 macrophages, is there a difference?” Upon investigation, Mitragotri and his team elucidated how macrophage phenotype alters its efficiency in tumor infiltration. Their findings, published in Applied Physics Reviews, offer insights into how macrophage dynamics may influence cell therapy development.3

Mitragotri’s team used murine breast cancer cells to form a 3D solid tumor model to assess the transport properties of macrophages. With this model, the team created a microenvironment suitable to compare naïve M0 and M1 macrophages. Researchers derived M1 macrophages by treating M0 macrophages with proinflammatory molecules such as interferon gamma and lipopolysaccharide.

Headshots of study authors Omokolade Adebowale (left), Jennifer Guerriero (center), and Samir Mitragotri (right).
Postdoctoral researcher Omokolade Adebowale from Harvard University (left), cancer biologist Jennifer Guerriero (center) from Dana-Farber Cancer Institute, and Samir Mitragotri (right) collaborated to bring physical and biological science together to better understand the dynamics of macrophage infiltration to tumors.
Omokolade Adebowale: Wesley Ford. Jennifer Guerriero:  Sam Ogden at Dana-Farber Cancer Institute. Samir Mitragotri: Eliza Grinnell at Harvard University

When placed together, the macrophages raced to the solid tumor. Over ten hours, the team tracked various movement metrics: macrophage displacement, total distance, and speed. The results surprised Mitragotri. He predicted that biological activation would lead to more activity of transport, but M0 macrophages outpaced M1 macrophages. 

Not only did M0 macrophages reach the tumor more quickly, but these naïve macrophages also infiltrated the tumor spheroids five times faster than activated macrophages. The macrophages also showcased morphological changes. 

“Looking at the world of cancer immunology and cell therapy, it is largely driven by biology. However, in addition to the biology of the cell, it is ultimately a transport problem of the cells getting into the tumor,” remarked Mitragotri.

The researchers used live imaging and machine learning algorithms to find a correlation between macrophage migration and shape variability. The data suggested that M0 macrophages possessed higher aspect ratios as they elongated and stretched out during migration.

“[Their] idea is good to address this question from a different angle, starting from a physics point of view of how cells migrate,” said Alok Mishra, a molecular immunologist at the University of Massachusetts who was not involved in the study. However, the findings left Mishra wanting more. “Physics in the biological system is very tricky and the study results are very preliminary.” 

Mitragotri acknowledged the study’s qualitative limitations but believes that their approach provides a foundation for further investigations. He plans to better understand how the activation status of macrophages couples with the transport function.

“One of the ways to potentially approach this is to collect information from smaller length scales to the larger scale. Then there can be a cohesive platform, and that's our vision to implement over the next many years,” said Mitragotri, who is optimistic about the combinatory prowess of computational platforms and experimental observation to more closely mimic in vivo conditions.

“We hope that this [study] inspires others, where the world of physics and biology can come together synergistically to try to understand these problems,” said Mitragotri.

References

  1. Andreesen R, et al. Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives. J Leukoc Biol. 1998;64(4):419–426.
  2. Lee S, et alMacrophage-based cell therapies: The long and winding road. J Control Release. 2016;240:527-540.
  3. Adebowale K, et al. Dynamics of macrophage tumor infiltrationAppl. Phys. Rev. 2023; 10(4): 041402.