In recent years, significant strides have been made in harnessing the body’s own immune system to combat cancer. A particularly promising approach, known as immune checkpoint blockade, functions by releasing what researchers describe as “brakes” on T cells, enabling them to more effectively recognize and destroy cancer cells. However, despite its success in some patients, many solid tumors – including the majority of breast cancers – remain largely resistant to this type of therapy. Researchers are now focusing on understanding the underlying reasons for this resistance, and a new study from the University of Illinois Urbana-Champaign suggests a key role for a protein called ABCA1.
The study, published in Science Advances, reveals that ABCA1, involved in transporting cholesterol out of immune cells called macrophages, appears to shift these cells into an “attack cancer” mode. This finding offers a potential new avenue for enhancing cancer immunotherapy, particularly for solid tumors that have historically proven difficult to treat.
“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,” says Erik Nelson, Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign. “While this approach works well for some patients, many so-called solid tumors fail to respond or develop resistance mechanisms.”
The research team’s investigation began with a focus beyond T cells, seeking to understand why solid tumors often fail to respond to conventional immunotherapy. Their attention turned to myeloid immune cells, specifically macrophages, which are abundant within the tumor environment and play a crucial role in shaping its characteristics. Macrophages can either promote or suppress immune responses, and understanding how to direct their activity is critical.
“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,” explains Nelson. “When we engineer macrophages to express more ABCA1, they become much better at fighting cancer and supporting the other immune cell type, T cells.”
Currently, immune checkpoint blockers are approved for only a limited subtype of breast cancer, and even within this group, only approximately one-quarter of patients experience a positive response to treatment. Researchers believe that the influence of myeloid cells within the tumor environment contributes significantly to this limited efficacy. These cells can suppress immune activity, encourage the growth of new blood vessels that nourish the tumor, and ultimately diminish the effectiveness of immunotherapy.
To determine the importance of ABCA1 in the immune response, the researchers conducted experiments using mice genetically engineered to lack ABCA1 in their myeloid cells. The results were striking: tumors grew more rapidly in these mice, and, crucially, immunotherapy proved ineffective in controlling tumor growth.
“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.”
Importantly, the team also found evidence supporting the relevance of these findings to human patients. Analysis of patient tumor samples revealed a correlation between higher levels of ABCA1 in myeloid immune cells and increased numbers of cancer-killing T cells, as well as improved outcomes for breast cancer patients.
“This tells us that what we are seeing in the lab is relevant to patients with cancer,” Nelson stated. “It gives us confidence that targeting ABCA1 could be a meaningful new strategy for cancer immunotherapy.”
The research team is now focused on developing methods to specifically increase ABCA1 activity within tumor-associated macrophages. They are also investigating whether combining these approaches with existing immunotherapies could further enhance treatment effectiveness. This work builds on findings from a study published in PubMed, which demonstrated that ABCA1 activity enhances the anticancer functions of macrophages, improving their ability to infiltrate tumors, reduce blood vessel growth, and support T cell activity.
“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.”
The implications of this research extend beyond breast cancer, suggesting a potential paradigm shift in how immunotherapy could be universally improved across a range of solid tumors. As researchers continue to unravel the complex interplay between cholesterol metabolism, immune cell function, and cancer progression, new and more effective treatment strategies may be within reach.
