In the May 10 issue of Science Immunology, researchers unveil a previously unknown tactic used by cancer tumors to dodge the body’s immune system.
The analysis by cancer researchers at Duke University School of Medicine and University of North Carolina Chapel Hill is a step forward in understanding why some cancers do not respond to immunotherapy.
They discovered that a specific type of cell that usually rallies to help the body fight foreign invaders, including cancer cells, can suddenly operate differently, and instead allow cancer to grow unchecked. Using mouse models, the team found dendritic cells can be successfully manipulated to prevent their rogue transformation.
“By disrupting the mechanisms that enable tumors to evade immune detection, we aim to expand the cancer patient population who can benefit from immunotherapy,” said senior study author and medical oncologist at Duke Cancer Institute Brent A. Hanks, MD, PhD, who has appointments in the Department of Medicine and Department of Pharmacology and Cancer Biology at Duke.
What causes the dendritic cells to shift roles starts with a strategy employed by tumors. Cancer tumors produce high levels of lactate that can reprogram healthy dendritic cells into what scientists termed “mregDCs.”
Unlike their healthy counterparts, mregDCs act as traitors, suppressing the body’s immune response, making it harder for the body to attack cancer cells.
“Probably the most surprising finding was that mregDCs aren’t just poor stimulators of T cells needed for an immune response, but they are also capable of blocking other conventional cells from doing their job of initiating an immune response,” said lead study author Michael P. Plebanek, PhD, a postdoctoral associate and cancer immunologist at Duke School of Medicine.
But researchers identified a molecular lynchpin in the plot: The lactate secreted by tumors activates a protein called SREBP2 within dendritic cells. This protein transforms normally helpful cells into something sinister.
By blocking the SREBP2 protein, either through targeted drugs or genetic silencing in mouse models of melanoma, researchers were able to prevent the transformation of dendritic cells into mregDCs.
This not only bolstered the ability to fight tumors but also significantly enhanced the efficacy of immunotherapy treatments, according to the study.
Authors note that tumors likely employ a variety of strategies to evade immune detection. But the discovery could lead to a new approach for targeted cancer therapies.
Additional authors include Yue Xue, PhD; Y-Van Nguyen; Nicholas C. DeVito, MD; and Balamayooran Theivanth, PhD, of the Duke Department of Medicine Division of Medical Oncology; Georgia Beasley, MD, in the Duke Department of Surgery and Alisha Holtzhausen, PhD, of UNC-Chapel Hill School of Medicine.