Cholesterol transporter ABCA1 boosts macrophage-driven cancer immunity

In recent years, cancer researchers have made major breakthroughs by using the body's immune system to fight cancer. One of the most promising approaches, known as immune checkpoint blockade, works by releasing molecular "brakes" on T cells. This allows them to better recognize and attack cancer cells. While these therapies can be very effective for some patients, many solid tumors, including most forms of breast cancer, remain largely unaffected. Cancer Center at Illinois (CCIL) Program Co-leader Erik Nelson and his research group are working to understand why these treatments fail.

Elevated blood concentrations of cholesterol have long been linked to cancer outcomes. In a new study, they found that a protein called ABCA1 is involved in transporting cholesterol out of a type of immune cell called macrophages, and in so-doing shifts them to an "attack cancer" mode.

Immune based therapies have revolutionized how we can treat cancer, basically taking the brakes off of a type of immune cell called T cells so they can attack cancer. While this approach works well for some patients, many so-called solid tumors fail to respond or develop resistance mechanisms."

Erik Nelson, Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Champaign

Nelson's team began looking beyond T cells to try and understand why solid tumors fail to respond to traditional treatments. They focused on myeloid immune cells, particularly macrophages, which are abundant in many solid tumors and play a major role in shaping the tumor environment.

"Here, we find that ABCA1, which is a protein that transports cholesterol from inside the cell to the outside, plays a big role in directing how myeloid cells, specifically macrophages, behave," Nelson said. "When we engineer macrophages to express more ABCA1, they become much better at fighting cancer and supporting the other immune cell type, T cells."

Immune checkpoint blockers are currently approved for only one subtype of breast cancer, and even among those patients, only about a quarter respond to treatment. One reason, researchers believe, is the influence of myeloid cells in the tumor environment. These cells can suppress immune activity, promote new blood vessel growth that feeds tumors, and limit the effectiveness of immunotherapy.

To understand how important ABCA1 is to the immune response, the team tested what happens when myeloid cells completely lack ABCA1.

"We next utilized mice that were engineered so that their myeloid cells did not express ABCA1," Nelson said. "Tumors grew quicker in these mice, and perhaps even more importantly, immune based therapies failed to control tumors in these mice."

The researchers also found strong evidence that these mechanisms matter in humans. In patient tumor samples, higher levels of ABCA1 in myeloid immune cells were associated with increased numbers of cancer killing T cells and improved outcomes for breast cancer patients.

"This tells us that what we are seeing in the lab is relevant to patients with cancer," Nelson said. "It gives us confidence that targeting ABCA1 could be a meaningful new strategy for cancer immunotherapy."

Looking ahead, Nelson's team is now focused on developing ways to increase ABCA1 activity specifically in tumor associated macrophages and testing whether these approaches can be combined with existing immune therapies.

"Our ultimate goal is to induce an immune response in tumors that were previously unresponsive to immunotherapy," Nelson said. "The immune system has the capacity to eradicate cancer. We just need to figure out where all the brakes are and how to release them safely."