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Cancer treatment could be transformed by shape-shifting macrophages

A new study could potentially revolutionize the field of cancer immunotherapy. Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have gained critical insights into the role of macrophages in cancer treatments. 

Macrophages, a type of white blood cells, have long been recognized for their potential in cell therapy due to their innate ability to infiltrate tumor cells. 

Despite showing promise in laboratory settings, their effectiveness in clinical trials has been disappointing, prompting researchers to seek answers beyond conventional biological explanations.

Physical barriers 

The research team, led by Samir Mitragotri, used an engineering approach to investigate the physical barriers hindering macrophages from reaching tumors. 

By integrating microscopy with machine learning, the experts discovered that certain macrophage phenotypes are more adept at traveling to tumors than others. Intriguingly, the phenotype commonly used in clinical cancer therapies is not the most effective one.

Key questions

“Our engineering approach led us to question whether the poor therapeutic outcome of macrophages in cell therapies can in part originate from their inability to get into the tumor in the first place,” said Mitragotri. 

“And indeed, our results show that different phenotypes exhibit different penetration into the tumor. This provides an interesting physics-based hypothesis for the poor clinical outcome of previously reported macrophage therapies and provides a counter- and complimentary hypothesis to the classical biology-based paradigm.”

Focus of the study 

Macrophages exist in multiple types, namely M0, M1, and M2. M1 macrophages, known for their tumor-fighting capabilities, have been predominantly used in cell therapies but with limited success in clinical trials. 

The researchers examined how these phenotypes navigated through a complex hydrogel to a tumor in a petri dish. 

Mapping system

“We basically wanted to measure how well the transport mechanics and GPS of these different macrophages worked in a complex environment,” explained study first author Kolade Adebowale, a postdoctoral fellow at SEAS.

“We found that the M1 phenotype, anti-tumor microphage, seem to have trouble finding their targets, almost like their GPS wasn’t working. But the M0 phenotype seemed to have a really good map.”

Critical insights 

The team uncovered a link between the macrophages’ ability to change shape and their transport efficiency. 

The M1 macrophages, which are most commonly used in therapies, are the least capable of shape-shifting, impacting their ability to reach tumors effectively.

Study implications 

This research not only challenges the existing biological perspectives but also opens new avenues for improving the efficacy of macrophage-based therapies in cancer treatment. 

“Our study demonstrates that the reduced transport of M1 macrophages compared to M0 macrophages is correlated with their reduced ability to undergo shape transformations,” said Adebowale. 

“We hope that these findings shed new light on the biophysics of macrophage migration and delivery of macrophage cell therapies.”

Tremendous potential 

Study co-author Jennifer Guerriero is an assistant professor at Harvard Medical School and the lead investigator of Brigham and Women’s Hospital Breast Oncology Program.

“There is tremendous potential in utilizing macrophages to mediate anti-tumor immune responses in human tumors and clinical trials are ongoing to treat patients with macrophages,” said Guerriero.

“We learned in this study that, surprisingly, macrophages that resemble an M0 phenotype were most efficient at getting to their target. These data will have an immediate impact on clinical trials are likely to transform the next generation of macrophage-mediated therapies.” 

The research was supported by the National Science Foundation.

The study is published in the journal Applied Physics Reviews.

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