Study sheds light on relationship between triple-negative breast cancer cells, immune systems

Indiana University School of Medicine cancer researchers say they now have a better understanding of why patients’ immune systems don’t attack triple-negative breast cancer cells in the same way as other types of cancer.

A new study in Nature from the laboratory of Reza Shahbazi, PhD, an assistant professor in the Division of Hematology/Oncology in Indiana University School of Medicine Department of Medicine, revealed that triple-negative breast cancer cells reprogram a patient’s white-blood T cells, making them less effective in fighting tumors caused by the disease.

Triple-negative breast cancer, or TNBC, is one of the most aggressive forms of breast cancer. Unlike many types of breast cancer, TNBC lacks the hormone receptors and HER2 proteins that are targeted by most effective breast cancer therapies; and although TNBC can trigger a strong immune response from patients, its tumors frequently find ways to weaken or escape those immune attacks.

Those factors make TNBC particularly difficult for doctors to treat. But Shahbazi said his team’s research sheds further light on the characteristics of TNBC cells, which will lead to more effective treatments in the future.

“Our findings show that tumors are not simply evading the immune system — they are actively reshaping it,” Shahbazi said. “By uncovering how cancer-derived exosomes reprogram T-cell function and immune recognition, and by identifying key genes, signaling pathways and candidate noncoding RNAs involved in this process, our study provides a roadmap for new therapeutic strategies that could help strengthen and refine future immunotherapies for triple-negative breast cancer.”

Shahbazi said his research team found that TNBC cells release tiny particles called exosomes that can enter T cells and reprogram how they function. The exosomes push T cells toward more regulatory, exhausted and dysfunctional states, reduced their ability to kill tumor cells, and altered key immune signaling pathways. They also found that tumor-derived exosomes can influence the T-cell receptor repertoire.

“This suggests that cancer can shape not only how immune cells behave, but also which T-cell populations expand and participate in the immune response,” Shahbazi said.

This research included collaboration with the lab of Lionel Apetoh, PhD, a member of the IU School of Medicine Department of Microbiology and Immunology, as well as researchers from the Brown Center for Immunotherapy and the Indiana University Melvin and Bren Simon Comprehensive Cancer Center.

Work in the Shahbazi Lab focuses on understanding and harnessing the power of immune engineering, cancer biology and regenerative medicine. The team applies cutting-edge technologies including CRISPR-based gene editing, exosome biology, single-cell multi-omics and advanced cell therapies to develop next-generation solutions for hematological malignancies, cancer and immune dysfunctions.

Shahbazi is an active member of the American Society of Gene and Cell Therapy (ASGCT). His work has resulted in multiple licensed patents.

Sanam Rezaei Benam, MS, served as the lead author on the paper, which was published in the journal Nature.

Rezaei Benam is a research analyst in the Shahbazi Lab and has made important contributions to this project, including isolating exosomes from cancer cell lines and patient samples, preparing noncoding RNA libraries, and studying the interactions of tumor-derived exosomes with human T cells.

“Her work was instrumental in helping us understand how these exosomes influence T-cell responses,” Shahbazi said.