April 19, 2021
Christy Hagan, PhD, has received a $450,000, three-year grant from the U.S. Department of Defense to study breast cancer cells and better understand their ability to evade the immune system.
Our immune system, a complex network of proteins and cells, constantly surveys the body looking for abnormal cells. Mutated cells, even in very small amounts, release danger signals recognized by the immune system. Once a tumor is recognized, immune cells destroy and clear the tumor cells. The immune system flags and disposes of mutated cells on a regular basis, however, some cancer cells may avoid detection and develop into tumors. Dr. Hagan, a member of The University of Kansas Cancer Center’s Cancer Biology research program, aims to understand how these cancer cells hide from the immune system – specifically the mechanisms downregulating these danger signals.
According to Dr. Hagan, discovering how cancer cells turn these signals off is the first step in designing therapies that prevent them from dodging the immune system. Her lab focuses on breast cancer and the role of progesterone, a hormone believed to play a part in hiding abnormal cells. Progesterone works by binding to a protein, the progesterone receptor, which in turn binds to DNA and turns on genes involved in cell growth and survival.
“Our lab has discovered that the progesterone receptor can turn off some of the danger signals the immune system relies on to recognize early tumors,” Dr. Hagan said. “We propose that blocking the progesterone receptor, thereby alerting the immune system to the presence of these early, small breast tumors, could be a novel mechanism for preventing and treating breast cancer.”
Switching cold tumors into hot ones
Recent advances in cancer treatment include immunotherapies aimed at re-activating the immune system to recognize and destroy tumors. Some cancers, such as melanoma and lung cancer, are highly responsive to immunotherapy. These immune “hot” tumors contain large amounts of T-cells that have infiltrated the tumor microenvironment to fight off cancerous cells. Immune checkpoint therapies work best in those tumors by reactivating the immune system to recognize and destroy the tumor. Breast cancer, however, is considered immune “cold,” and is less likely to respond to immune checkpoint therapies.
“In preclinical studies, progesterone has been shown to promote changes in the immune system that lead to downregulated immune activity. Our preliminary data illustrates that, in the breast, progesterone tamps down the immune cells’ response. These changes in the tumor microenvironment of the breast could result in an immune ‘cold’ microenvironment” Dr. Hagan said.
Using animal models, Dr. Hagan and her team will monitor how progesterone receptor expression and activation influences the cancerous cells’ ability to hide from the immune system.
“By better understanding how progesterone receptor controls the immune system in the breast, we may be able to develop novel therapies to target it, priming the immune system to be more receptive to immunotherapy,” Dr. Hagan said. “Ultimately, we hope to convert breast cancer from immune cold to hot, making it more responsive to immune-based therapies.”