Reprogramming compromised immune cells to fight cancer

Northwestern Medicine investigators have developed a new avenue to reprogram compromised immune cells to act against tumors, according to a study published in Science Advances.

Shana Kelley, Ph.D., the Neena B. Schwartz Professor of Chemistry, Biomedical Engineering, and of Biochemistry and Molecular Genetics, was senior author of the study.

Previous research in the Kelley lab revealed that in late-stage cancer, tumors’ treatment resistance is increased when they express more of the protein VISTA, which regulates immune cell activity. By increasing VISTA expression, tumors essentially “hijacked” macrophages—a type of white blood cell responsible for killing and removing dead cells—and recruited them to support the tumors’ growth.

“What’s interesting about the protein is that it modulates macrophages within the tumor environment and instead of being anti-tumor as they should be, they become more pro-tumor,” said Abdalla Abdrabou, a postdoctoral fellow in the Kelly lab and first author of the study.

In the current study, investigators sought to better understand this process and test ways to turn the macrophages back into healthy anti-tumor cells.

First, investigators performed a genome-wide CRISPR knockout screen to identify proteins that regulate VISTA levels; the team found that the presence of proteins AhR and IRAK1 appeared to have an impact on VISTA levels.

Next, the scientists used CRISPR-Cas9 gene editing to remove AhR and IRAK1 from human blood cell samples. Without the proteins, VISTA levels dropped.

Finally, investigators inhibited AhR and IRAK1 in mice with late-stage tumors and found that the combination therapy significantly increased survival and slowed progression of the tumor.

The findings highlight a potential path forward for treating late-stage tumors that have become resistant to current therapies, Abdrabou said.

“Most immunotherapy strategies right now are trying to remove roadblocks, for example, immune checkpoint blockade therapy,” Abdrabou said. “We’re not removing the roadblocks per se, but we’re trying to reprogram cells that the cancer managed to recruit back to being anti-tumor again.”

Moving forward, investigators will test the therapy in other cancer models and study the long-term effects, Abdrabou said.

“We’re really excited about the results, but at the same time we appreciate that cancer is a complex disease,” Abdrabou said. “We look at every cancer as its own disease and will continue to look into new technologies to dissect every cancer on its own.”

Northwestern Medicine investigators have developed a new avenue to reprogram compromised immune cells to act against tumors, according to a study published in Science Advances.

Shana Kelley, Ph.D., the Neena B. Schwartz Professor of Chemistry, Biomedical Engineering, and of Biochemistry and Molecular Genetics, was senior author of the study.

Previous research in the Kelley lab revealed that in late-stage cancer, tumors’ treatment resistance is increased when they express more of the protein VISTA, which regulates immune cell activity. By increasing VISTA expression, tumors essentially “hijacked” macrophages—a type of white blood cell responsible for killing and removing dead cells—and recruited them to support the tumors’ growth.

“What’s interesting about the protein is that it modulates macrophages within the tumor environment and instead of being anti-tumor as they should be, they become more pro-tumor,” said Abdalla Abdrabou, a postdoctoral fellow in the Kelly lab and first author of the study.

In the current study, investigators sought to better understand this process and test ways to turn the macrophages back into healthy anti-tumor cells.

First, investigators performed a genome-wide CRISPR knockout screen to identify proteins that regulate VISTA levels; the team found that the presence of proteins AhR and IRAK1 appeared to have an impact on VISTA levels.

Next, the scientists used CRISPR-Cas9 gene editing to remove AhR and IRAK1 from human blood cell samples. Without the proteins, VISTA levels dropped.

Finally, investigators inhibited AhR and IRAK1 in mice with late-stage tumors and found that the combination therapy significantly increased survival and slowed progression of the tumor.

The findings highlight a potential path forward for treating late-stage tumors that have become resistant to current therapies, Abdrabou said.

“Most immunotherapy strategies right now are trying to remove roadblocks, for example, immune checkpoint blockade therapy,” Abdrabou said. “We’re not removing the roadblocks per se, but we’re trying to reprogram cells that the cancer managed to recruit back to being anti-tumor again.”

Moving forward, investigators will test the therapy in other cancer models and study the long-term effects, Abdrabou said.

“We’re really excited about the results, but at the same time we appreciate that cancer is a complex disease,” Abdrabou said. “We look at every cancer as its own disease and will continue to look into new technologies to dissect every cancer on its own.”