About 50% of triple-negative breast cancer (TNBC) patients develop resistance to therapy. When resistance arises, tumors 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 tumor 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 Center and member of the Dan L Duncan Comprehensive Cancer Center, all 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."
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 tumors, 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 tumors, 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 tumors escape the immune response against them," said co-first author Dr. Liqun Yu, postdoctoral fellow in the Zhang lab. "Reprogramed 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 several ways to counteract the actions of the suppressive macrophages in mesenchymal-like tumors. Removing macrophages or blocking their recruitment into tumors restored the cancer's sensitivity to treatment. Blocking compounds produced by suppressive macrophages restored immune response against the tumors, 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 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 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 Center - Houston.
This work was supported by funding from the National Institutes of Health (grants CA125123, RR024574 and S10OD025240), Department of Defense (grants DAMD W81XWH-16-1-0073 and DAMD W81XWH-20-1-0375783), National Cancer Institute (grants CA183878, CA251950, CA221946, CA227904, CA253533, P50CA186784 and 1F31CA281063-01A1), Breast Cancer Research Foundation (grant BCRF-24-178) and Cancer Prevention and Research Institute of Texas (grants RP200504 and RP180672).
