About 50% of triple-negative breast cancer (TNBC) patients develop resistance to therapy.

When resistance arises, tumours are more likely to come back after the original treatment, significantly reducing the chances of survival.

Researchers at Baylor College of Medicine have discovered that there is more than one way TNBC can become immune to therapy.

Their study, published in the Journal of Clinical Investigation, reveals two mutually exclusive mechanisms that can give TNBC the ability to survive therapy.

The findings have implications for treatment.

Knowing ahead of time which resistance mechanism a patient’s tumour is likely to implement can guide treatment decisions 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 corresponding author 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 Centre and member of the Dan L Duncan Comprehensive Cancer Centre, all at Baylor.

“Not every TNBC tumour is the same. Each one has a particular cellular composition of tumour cells and immune cells, such as macrophages and neutrophils. Depending on this composition, a tumour may follow a different path to develop resistance.”

The researchers investigated resistant pathways working with patient tissue samples and mouse models.

In their previous study they had shown that in TNBCs called epithelial-like tumours, containing macrophages and neutrophils, the latter play a major role in resistance to therapy.

But in the current study, the team discovered that neutrophils are not always the ones leading toward a path of resistance.

In other TNBCs, called mesenchymal-like tumours, containing mostly macrophages, these immune cells play a major role in developing resistance.

“We found that chemotherapy can reprogram the macrophages, transforming them from a cell that typically fights disease into one that helps tumours escape the immune response against them,” said co-first author 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 tumour.”

The researchers tested several ways to counteract the actions of the suppressive macrophages in mesenchymal-like tumours.

Removing macrophages or blocking their recruitment into tumours restored the cancer’s sensitivity to treatment.

Blocking compounds produced by suppressive macrophages restored immune response against the tumours, which suggests potential strategies for preventing cancer from becoming resistant to therapy.

The findings point out a potential new approach to treatment.

“If we can predict the possible therapy resistance path a tumour may follow by analysing its cellular composition before treatment, we could take actions to prevent resistance, which would increase the chances of patient survival,” Zhang said.

Other contributors to this work include co-first author 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, all at Baylor College of Medicine.

Co-author Bo Wei is at the University of Texas MD Anderson Cancer Centre – Houston.

Source: Baylor College of Medicine