In the fight against metastatic cancer, harnessing a patient’s own immune system to target cancer cells has been a promising strategy.
In a recent article published in Cell Metabolism, Xin Lu, the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences at the University of Notre Dame and collaborators have made a breakthrough in understanding why a certain type of therapy is not always effective—and are now targeting a path to improve upon it.
Immune checkpoint blockade (ICB) therapy involves the use of drugs that enhance the activity of T cells, which are a type of immune cell that can kill cancer cells when activated. While ICB therapy is very effective for treating certain types of cancer, other cancers, such as metastatic breast cancer, are often not cured by the treatment, Lu said. Metastatic breast cancer is an advanced stage of breast cancer where tumor cells leave the primary tumor and migrate to other areas of a patient’s body. To understand why ICB therapy fails in this context, Lu and collaborators targeted neutrophils, an immune cell that can interfere with ICB therapy.
“Neutrophils pose a major threat to patients because they often display an unwanted activity toward T cells: they suppress T cells so that they lose the ability to kill cancer cells,” Lu said. The research team hypothesized that tumor-infiltrating neutrophils survive and continue to suppress T-cells in metastatic breast cancer tumors by altering their metabolism.
Using new sequencing technology, the researchers identified a metabolic enzyme called aconitate decarboxylase 1 (Acod1) that is present at much higher levels in neutrophils associated with metastatic breast cancer tumors, compared to neutrophils elsewhere in the body.
“Higher levels of Acod1 in tumor-infiltrating neutrophils brings them a big benefit: it allows them to survive in the stressful metastasis environment,” said Yun Zhao, the first author on the study and a postdoctoral scholar in Lu’s lab.
If the researchers deleted Acod1 in neutrophils, Zhao described, the tumor-associated neutrophils entered ferroptosis, a special type of iron-dependent cell death, which caused those cells to diminish quickly from the body. Mice with neutrophils lacking Acod1 responded favorably to ICB therapy, which reduced or eliminated their metastases.
The researchers found that tissue samples from human breast cancer patients also contained neutrophils with high levels of Acod1, indicating that the enzyme likely plays a similar role in human disease. According to Lu, understanding the effect of high Acod1 levels has created the potential for a promising new treatment approach.
“Once we identify a way to target Acod1 pharmacologically—a work that is underway right now in my lab—we should be able to combine the Acod1-targeting drug with ICB therapy to treat patients,” Lu said. “This combination treatment should be quite safe and should greatly enhance the response to ICB therapy.”
Lu acknowledged the importance of his collaborators on the study, which involved thirty authors from multiple institutions.
“Collaboration is absolutely essential for this work, and Notre Dame has a great environment for barrier-free collaboration,” Lu said. “I am particularly grateful for the support of Sharon Stack, the Ann F. Dunne and Elizabeth Riley Director of Harper Cancer Research Institute, Kleiderer-Pezold Professor of Chemistry & Biochemistry professor and Director of the Harper Cancer Research Institute, who tirelessly seeks and fosters collaborative opportunities for our cancer research community, and for the multiple groups outside of Notre Dame that provided essential contributions for this study.”
Collaborators on the study include Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Xuemin Lu, Toni Mayberry, M. Sharon Stack, Dailin Gan, Jun Li, and Jun Wan from the University of Notre Dame. Other partners included researchers from Indiana University - Purdue University Indianapolis, Indiana University School of Medicine, Rutgers Cancer Institute of New Jersey, University of Texas Southwestern Medical Center, and the Van Andel Institute. A full list of individual collaborators can be found on the research article website.
The study was supported by the National Institutes of Health (grants: R01CA280097 and R01CA248033 (Xin Lu) and P30CA082709 (Jun Wan)), the Susan G. Komen Foundation (grant: CCR18548293 (Xin Lu)), a METAvivor Early Career Investigator Award (Yun Zhao), the Department of Defense (grants: W81XWH2010312, W81XWH2010332, and HT94252310010 (Xin Lu)), and the Boler Family Foundation (Xin Lu) at the University of Notre Dame.