Indianapolis – Researchers at Indiana Melvin University and the Bryn Simon Comprehensive Cancer Center have identified how breast cancer cells hide from immune cells to stay alive. This discovery may lead to better immunotherapy for patients.
Xinna Zhang, Ph.D., and her colleagues found that when breast cancer cells have an increased level of a protein called MAL2 on the cell’s surface, the cancer cells can avoid immune attacks and continue to grow. The results were published this month in The Journal of Clinical Investigation And it appeared on the cover of the magazine.
The study lead author, Zhang is a member of the IU Simon Comprehensive Cancer Center and an assistant professor of medical and molecular genetics at IU Medical College.
Given the future of cancer treatment, immunotherapy harnesses the body’s immune system to target and destroy cancer cells. Understanding how cancer cells avoid immune attacks could provide new ways to improve immunotherapy for patients, explained Xiongbin Lu, PhD, Vera Bradley Foundation Professor of Breast Cancer Innovation and Cancer Center Researcher.
“The current cancer immunotherapy has impressive results in some patients, but more than 70% of breast cancer patients do not respond to cancer immunotherapy,” Luo said. “One of the biggest reasons is that tumors develop a mechanism to ward off immune attacks.”
The collaborative research team set out to answer key questions: How do breast cancer cells develop this immune evasion mechanism, and could targeting this action improve immunotherapies?
Zhang and Lu, two members of the Vera Bradley Foundation’s Center for Breast Cancer Research, turned to biomedical data researcher Chi Zhang, Ph.D., assistant professor of medical and molecular genetics at IU Medical School. Chi Zhang developed a computational method to analyze data sets from more than 1,000 breast cancer patients through a cancer genome atlas. This analysis led researchers to MAL2; It showed that elevated levels of MAL2 in breast cancer, especially in triple-negative breast cancer (TNBC), were associated with impaired patient survival.
“Dr. Zhang used his advanced computational tool to build a bridge between cancer genes, cancer genomics and clinical outcomes. We could analyze the molecular features of thousands of breast tumor samples to identify potential cancer immunotherapy targets. From this data, MAL2 was the highest ranking gene that we wanted to study.”
Xinna Zhang took that data to her lab to determine the purpose of MAL2 in cells, how it affects the growth of breast cancer cells and how it interacts with immune cells. Using breast cancer tissue samples from IU patients, cell models, and animal models, I found that breast cancer cells express more MAL2 than normal cells. It also discovered that high levels of MAL2 greatly promoted tumor growth, while inhibition of the protein could almost completely halt tumor growth.
In Luo’s lab, he used a patient-derived 3D model called organo to better understand how minimizing MAL2 improves patient outcomes.
“Cancer cells can avoid immune attacks; with less MAL2, cancer cells can be identified and killed by the immune system.” MAL2 is a new target. By determining its function in cancer cells and cancer immunology, we now know its potential as a cancer immune target. “
Researchers are now exploring ways that these results can be used to develop and improve treatments for breast cancer.
Luo co-leads a triple-negative breast cancer immunotherapy program as part of the Indiana University’s Micro Health Initiative. Xinna Zhang and Chi Zhang are also involved in the initiative to develop a new breast cancer immunotherapy treatment. The Micro Health Initiative, the first recipient of funding from the Grand Challenges Program at Indiana University, promotes the prevention, treatment and health outcomes of human diseases through more accurate analysis of the genetic, developmental, behavioral and environmental factors that shape an individual’s health. .
Additional authors are Bryan P. Schneider, MD, Yunlong Liu, PhD, and Sha Cao, PhD, of IU Simon Comprehensive Cancer Center; Yuanzhang Fang, PhD, Lifei Wang, Changlin Wan, Yifan Sun, Kevin Van der Jeught, PhD, Zhuolong Zhou, PhD, Tianhan Dong, Ka Man So, Tao Yu, PhD, Yujing Li, PhD, Haniyeh Eyvani, Austyn B. Colter Edward Dong, George E. Sandusky, Ph.D. from IU Medical School; And Jin Wang, Ph.D., from Baylor College of Medicine.
This study was supported by the Vera Bradley Breast Cancer Research Foundation, the American Cancer Society Institutional Research Grant, and the National Institutes of Health (R01CA203737 and R01CA206366).
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