Research shows how breast cancer cells evade immune attacks

Scientists from the Indiana University (IU) Melvin and Bren Simon Comprehensive Cancer Center have discovered how breast cancer cells evade immune cells to survive. The findings could lead to more improved immunotherapy treatment for patients.

Xinna Zhang, PhD. Image Credit: Indiana University School of Medicine.

Xinna Zhang, Ph.D., and collaborators observed that when breast cancer cells have higher concentrations of the protein, known as MAL2 on the surface of cells, the tumor cells can continue to grow by evading immune attacks. The study results were recently published in The Journal of Clinical Investigation and appeared on the cover of the journal.

Like other cancer cells, breast cancer cells present tumor-specific antigens on the cell membrane, which immune cells recognize so they can kill the tumor cells. But our study found that MAL2 can reduce the level of these antigens, so these tumor cells are protected and can no longer be recognized as a threat by these immune cells.”

Xinna Zhang, PhD, Study Lead Author, Indiana University School of Medicine

Zhang is also a member of the IU Simon Comprehensive Cancer Center and an assistant professor of medical and molecular genetics at IU School of Medicine.

Immunotherapy is regarded as the future of cancer treatment. It targets and kills cancer cells by harnessing the body’s immune system. Interpreting how cancer cells evade immune attacks could provide new ways to enhance immunotherapy for patients, described Xiongbin Lu, Ph.D., Vera Bradley Foundation Professor of Breast Cancer Innovation and cancer center researcher.

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

Xiongbin Lu, PhD, Professor, Vera Bradley Foundation Center for Breast Cancer Research, Indiana University School of Medicine

The joint research group set out to answer crucial questions—how do breast cancer cells acquire this immune evasion mechanism, and whether targeting that action could result in enhanced immunotherapies?

Zhang and Lu, members of the Vera Bradley Foundation Center for Breast Cancer Research, sought the help of Chi Zhang, Ph.D., a biomedical data researcher and an assistant professor of medical and molecular genetics at IU School of Medicine. Zhang created a computational technique to examine data sets from over 1,000 breast cancer patients via The Cancer Genome Atlas.

That study led the team to the MAL2 protein; it revealed that increased levels of the MAL2 protein in breast cancer, and particularly in triple-negative breast cancer (TNBC), was associated with poorer survival of patients.

Dr. Chi Zhang used his advanced computational tool to build a bridge that connects cancer genetics and cancer genomics with a clinical outcome. We can analyze molecular features from thousands of breast tumor samples to identify potential targets for cancer immunotherapy. From that data, MAL2 was the top-ranked gene that we wanted to study.”

Xiongbin Lu, PhD, Professor, Vera Bradley Foundation Center for Breast Cancer Research, Indiana University School of Medicine

Zhang took that data to her laboratory to establish the purpose of the MAL2 protein in the cells, how it influences the growth of breast cancer cells, and how it communicates with immune cells. She used breast cancer tissue specimens from animal models, cell models, and IU patients, and found that breast cancer cells express a higher amount of MAL2 protein than normal cells.

Zhang also found that increased levels of MAL2 considerably improved the growth of a tumor, while blocking the protein can almost completely cease the growth of a tumor.

In Lu’s laboratory, Zhang employed a 3D, patient-derived model known as an organoid to gain a deeper understanding of how decreasing the MAL2 could improve outcomes in patients.

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