Scaffold tumor formation paves way for better immunotherapies

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Newswise – The gap between preclinical advances in breast cancer immunotherapy and poor patient outcomes is rooted in the limitations of current breast cancer models. These models often fail to mimic the complex interactions between cancer cells and key immune cells present in the tumor microenvironment.

Using a collaborative approach, Susan N. Thomas, associate professor at the George W. Woodruff School of Mechanical Engineering at the Georgia Institute of Technology, and former doctoral student Meghan O’Melia developed a new way to generate larger breast tumor models. quickly and more reliably. , and with considerably less immune variability than existing models. Their groundbreaking research, published in the January issue of Advanced materialshas the potential to revolutionize the development of immunotherapy treatments and may also help understand why patients with the same type of breast cancer respond differently to treatment.

By using a gel-like matrix as a scaffold to grow breast cancer tumors, Thomas and O’Melia were able to modulate how immune cells filter through a tumor’s microenvironment. In doing so, they have created tumor models that are exceptionally well suited for immunotherapy drug testing. Additionally, by modifying the scaffold, they were able to replicate the immune microenvironments seen in patients with treatment-resistant breast cancer.

“This work provides us with new models to understand how tumor microenvironments influence responses to immunotherapies,” said O’Melia, now a postdoctoral fellow at Harvard. “We see potential for predicting, based on the immune characteristics of a patient’s tumor, which treatment that person will respond best to.”

Limitations of breast cancer models

Current advanced models of breast cancer have major drawbacks. One type of model involves injecting human tumor cells into mice that lack a full immune system, but this complicates the study of immune-targeting therapies. In a different approach, mice are manipulated at the genome level to make them prone to cancer. Although their immune responses may closely resemble those of human patients, the rate of tumor development is highly variable, making these models suboptimal for evolutionary drug testing.

However, the most common way to generate breast cancer models for immunotherapy research is to inject mouse breast cancer cells directly into healthy mice. This method is affordable and scalable, but sometimes up to 80% of mice in an experiment will not develop tumors.

To address this problem, breast cancer researchers began injecting the tumor cells alongside a commercially available gel-like protein mixture derived from mouse cells (Matrigel), which helps tumors grow reliable. The problem with the mixture, however, is that its composition varies from batch to batch. Using the mixture therefore creates more unknown variables, affecting a mouse’s immune response in unpredictable ways.

An unexpected solution presented itself when Thomas and O’Melia attended a regenerative medicine workshop. At the workshop, Edward Botchwey, associate professor in the Walter H. Coulter Department of Biomedical Engineering, presented a bioengineering scaffold capable of modulating how immune cells filter into a wound site to facilitate tissue healing. .

“I turned to Meghan and said, ‘Why don’t we see if they want to collaborate to explore if we can change the way immune cells are recruited to the site where we implant our tumors? ‘” Thomas said.

They set out to work with Botchwey and Andrés García, professor of mechanical engineering and executive director of the Parker H. Petit Institute for Bioengineering and Bioscience (IBB), to develop a scaffold to grow breast tumors.

A new scaffold to shape the tumor microenvironment

The team developed their own synthetic jelly-like matrix. They then injected cells from triple-negative breast cancer (TNBC), the most aggressive type of breast cancer, alongside the matrix as scaffolding to help them grow. They found that their breast cancer tumors grew at a 100% rate and did so faster and with less variability in growth than when using Matrigel. More importantly, their scaffold limited the type of immune cells that infiltrated the tumor microenvironment. Their approach resulted in the kind of controlled environment ideal for immunotherapy drug testing experiments.

To go further, the team created different formulations of the gel matrix by incorporating biomolecular tags easily recognized by immune cells. The tags are made of peptides and serve to recruit key immune cells from the microenvironment. Incorporating the beacons allowed Thomas and O’Melia to model different subtypes of immune environments often seen in treatment-resistant TNBCs.

They then tested two of the most common types of immunotherapy drugs — vaccines and immune checkpoint blockade therapy — on the different subsets of cancer microenvironments.

“When we used different matrix components, we saw different effects of these drugs on the same type of cancer,” Thomas said. “There is great variability related to why some patients respond or not respond to treatment, and until now there was no way to incorporate this into our mouse models during drug development.”

Look beyond the lab

The results demonstrate the critical role that a patient’s tumor immune microenvironment plays in the success of immunotherapies, highlighting the importance of their novel approach for future drug testing.

Thomas and O’Melia’s work has broad potential for prescreening immunotherapy drugs for individual patients. In theory, for the average cancer patient, a clinician could take a simple biopsy, determine which immune cells are present, and choose a better therapy.

They also collaborated with Levi Wood, assistant professor of mechanical engineering, and BWI researchers who contributed immune phenotyping for the experiments.

“Basically, by using established technology but applied in a new way, we’ve created a new tool to solve an old problem,” Thomas said. “The collaborative nature of this project was spectacular, and it’s really intrinsic to the Georgia Tech community.”

Susan N. Thomas is Associate Professor at the George W. Woodruff School of Mechanical Engineering and Woodruff Professor at the College of Engineering.

Edward Botchwey is an Associate Professor in the Walter H. Coulter Department of Biomedical Engineering.

Andrés J. García is Executive Director of BWI, Little Director’s Chair in Bioengineering and Biosciences, and Full Professor at the George W. Woodruff School of Mechanical Engineering.

Levi Wood is an assistant professor at the George W. Woodruff School of Mechanical Engineering.

QUOTE: Meghan J. O’Melia, Adriana Mulero-Russe, Jihoon Kim, Alyssa Pybus, Deborah DeRyckere, Levi Wood, Douglas K. Graham, Edward Botchwey, Andrés J. García and Susan N. Thomas, “Microenvironment synthetic matrix scaffolds in vivo tumor immune system for screening by immunotherapy”, Advanced materials (January 6, 2022).

DO I: https://doi.org/10.1002/adma.202108084

FUNDING: Grants from the United States National Institutes of Health: R01CA207619 (SNT), U01CA214354 (SNT), R01AR062920 (AJG), R01AR062368 (AJG), S10OD016264 (AJG), T32GM008433 (MJO) and T32EB006343 (AMR)

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