Immune checkpoint inhibitors (ICIs) are a form of immunotherapy that activates anti-tumor immune cells. In the context of cancer, many healthy cells cannot recognize and target tumors. This immune evasion is due to various mechanisms that the tumor employs to escape detection. On the surface of tumors there are markers that inactivate specialized immune cells, known as T cells. Consequently, T cells fail to recognize and target tumors. ICIs overcome this obstacle to immunotherapy by blocking surface protein interactions. Clinical trials have demonstrated that this therapy combined with other cancer treatments can significantly improve outcomes. However, even though combination therapy enhances treatment in the clinic, efficacy is still limited. Scientists are working to improve these therapies and enhance anti-tumor immunity.
A recent article in Science Advances, by Dr. Erik Nelson and others, demonstrated that a novel protein transports cholesterol out of immune cells to make them more anti-tumor-like. It has previously been reported that increased cholesterol concentrations are predictive of therapeutic outcomes in patients with cancer. This protein, known as ABCA1, drives the process that secretes cholesterol out of macrophages, a specialized immune cell. Consequently, macrophages then gain the ability to recognize and target the tumor. Nelson is a Professor and Research Program Leader at the Cancer Center at University of Illinois Urbana-Champaign. He is an endocrinologist and an expert in pharmacology. Nelson’s research focuses on different approaches to improve breast cancer treatment. Currently, his team is working on novel chemopreventative strategies to reduce mortality and improve patient survival.
Current immunotherapies have revolutionized the way doctors treat patients. However, efficacy is still limited due to the complex tumor microenvironment and various mechanisms that cancers employ to evade detection. As researchers looked closer, they found that macrophages play a critical role in antitumor immunity. Moreover, ABCA1 drives how macrophages function in response to cancer. Nelson and his group found that if they engineer macrophages to express more ABCA1, then the cells retain antitumor functions and improve other immune cell functions responsible for fighting cancer.
Engineered macrophages with more ABCA1 enhanced ICI therapy. Currently, only one type of breast cancer is approved for ICI treatment. However, this is in combination with standard-of-care therapy. Scientists believe that ICI efficacy is limited because of other cells, such as macrophages. These cells inhibit ICI’s from functioning properly to elicit strong antitumor immunity. For example, macrophages can suppress immune activity, drive blood vessel growth around the tumor, and polarize other cells to promote tumor growth. To understand the impact of ABCA1 on macrophages, researchers engineered a mouse to lack the protein. As a result, the tumors grew fasters and immunotherapies did not work. When ABCA1 was highly expressed, researchers observed opposite effects. They also saw similar results in samples from patients with cancer.
Nelson and his team are the first to demonstrate the role of ABCA1 on macrophages in the context of cancer immunotherapy. This work provides insight into macrophage biology and how to better enhance current ICIs. The team hopes to use this knowledge to develop therapeutic strategies that would improve patient survival. Overall, the group’s work has the potential to change standard-of-care therapy in patients with malignant solid tumors.
Article, Science Advances, Erik Nelson, University of Illinois Urbana-Champaign
