About half of patients with triple-negative breast cancer (TNBC) develop resistance to therapy, making it more likely for tumors to return after initial treatment and lowering survival rates. Researchers at Baylor College of Medicine have identified that TNBC can become resistant through two distinct mechanisms.
The study, published in the Journal of Clinical Investigation, describes how these two mutually exclusive resistance pathways could affect treatment decisions. Understanding which mechanism a patient’s tumor might use could help guide therapies to prevent or reduce resistance.
“We have learned from the current study, together with a previous study from our lab, that there is more than one way for TNBC to become resistant to therapy,” said Dr. Xiang Zhang, professor and William T. Butler, M.D., Endowed Chair for Distinguished Faculty in molecular and cellular biology, director of the Lester and Sue Smith Breast Center and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Not every TNBC tumor is the same. Each one has a particular cellular composition of tumor cells and immune cells, such as macrophages and neutrophils. Depending on this composition, a tumor may follow a different path to develop resistance.”
Researchers examined tissue samples from patients as well as mouse models. Previous work by the team showed that in epithelial-like TNBCs containing both macrophages and neutrophils, neutrophils play a key role in therapy resistance.
In their latest findings, they discovered that neutrophils are not always responsible for resistance. In mesenchymal-like tumors composed mainly of macrophages, these immune cells drive resistance instead.
“We found that chemotherapy can reprogram the macrophages, transforming them from a cell that typically fights disease into one that helps tumors escape the immune response against them,” said Dr. Liqun Yu, postdoctoral fellow in the Zhang lab. “Reprogrammed macrophages engulfed and eliminated cancer cells but also produced a variety of compounds, including C1q and resolvin, that suppressed the immune attack against the tumor.”
The researchers tested approaches to counteract suppressive macrophages in mesenchymal-like tumors. They found that removing macrophages or blocking their recruitment restored sensitivity to treatment. Blocking certain compounds produced by these macrophages also revived immune responses against tumors.
“If we can predict the possible therapy resistance path a tumor may follow by analyzing its cellular composition before treatment, we could take actions to prevent resistance, which would increase the chances of patient survival,” Zhang said.
Other contributors included Charlotte Helena Rivas; Fengshuo Liu; Yichao Shen; Ling Wu1; Zhan Xu; Yunfeng Ding; Xiaoxin Hao; Weijie Zhang; Hilda L. Chan; Jun Liu; Yang Gao; Luis Becerra-Dominguez; Yi-Hsuan Wu; Siyue Wang; Tobie D. Lee; Xuan Li; Xiang Chen and David G. Edwards at Baylor College of Medicine as well as Bo Wei at University of Texas MD Anderson Cancer Center – Houston.
Funding came from several sources including National Institutes of Health grants CA125123, RR024574 and S10OD025240 among others.
Baylor College of Medicine is an independent health sciences university focusing on research advancement, education across its schools and community service while providing patient care through partnerships (source). The institution collaborates within integrated health science environments (source) and Paul Klotman serves as president (source).
