IU researchers identify how breast cancer cells escape immune attacks

Indiana University researchers Melvin and Bren Simon Comprehensive Cancer Center have identified how breast cancer cells hide from immune cells to stay alive. The discovery could lead to better immunotherapy treatment for patients.

Xinna Zhang, PhD, and colleagues found that when breast cancer cells have an increased level of a protein called MAL2 on the cell surface, cancer cells can escape immune attacks and continue to grow. The results are published this month in The Journal of Clinical Investigation and featured on the newspaper cover.

The lead author of the study, Zhang is a fellow of the IU Simon Comprehensive Cancer Center and an assistant professor of medical and molecular genetics at the IU School of Medicine.

Considered the future of cancer treatment, immunotherapy harnesses the body’s immune system to target and destroy cancer cells. Understanding how cancer cells prevent immune attacks could offer new ways to improve immunotherapy for patients, explained Xiongbin Lu, PhD, professor of breast cancer innovation at the Vera Bradley Foundation and researcher at the Cancer Center. .

“Current cancer immunotherapy has wonderful results in some patients, but more than 70% of breast cancer patients do not respond to cancer immunotherapy,” Lu said. “One of the main reasons is that tumors develop a mechanism to escape immune attacks. “

The collaborative research team attempted to answer key questions: How do breast cancer cells develop this immune evasion mechanism, and could targeting this action lead to better immunotherapies?

Zhang and Lu, members of the Vera Bradley Foundation Center for Breast Cancer Research, turned to biomedical data researcher Chi Zhang, PhD, assistant professor of medical and molecular genetics at the IU School of Medicine. Chi Zhang developed a computational method to analyze data sets from more than 1,000 breast cancer patients using the Cancer Genome Atlas. This analysis led the researchers to MAL2; it showed that higher levels of MAL2 in breast cancer, and in particular in triple negative breast cancer (TNBC), were linked to lower patient survival.

Dr Chi Zhang used his advanced computational tool to build a bridge that links cancer genetics and cancer genomics to a clinical outcome. We can analyze the molecular characteristics of thousands of breast tumor samples to identify potential targets for cancer immunotherapy. Based on these data, MAL2 was the highest ranked gene we wanted to study. “

Xiongbin Lu, PhD, Vera Bradley Foundation Professor of Breast Cancer Innovation and Researcher at the Cancer Center

Xinna Zhang brought this 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 UI patients, cell models, and animal models, she found that breast cancer cells express more MAL2 than normal cells. She also found that high levels of MAL2 dramatically improved tumor growth, while inhibition of the protein could almost completely stop tumor growth.

In Lu’s lab, he used a three-dimensional model derived from the patient called an organoid to better understand how reducing MAL2 could improve patient outcomes.

“Tumor cells can evade immune attacks; with less MAL2, cancer cells can be recognized and killed by the immune system,” Lu said. “MAL2 is a new target. By identifying its function in cancer cells and l immunology of cancer, we now know its potential as a target for cancer immunology. “

Researchers are currently exploring ways to use these findings to develop and improve breast cancer therapies.

Lu co-leads a cancer immunotherapy program for triple negative breast cancer under the Indiana University Precision Health Initiative. Xinna Zhang and Chi Zhang are also participating in the initiative to develop a new immunotherapy against breast cancer. The Precision Health Initiative, the first recipient of funding from Indiana University’s Grand Challenges program, improves prevention, treatment and health outcomes of human diseases through more precise analysis of genetic factors, developmental, behavioral and environmental factors that shape the health of an individual. .