How neutrophils help triple-negative breast cancer cells spread

Researchers at Baylor College of Medicine and collaborating institutions have discovered how immune cells called neutrophils can help triple-negative breast cancer (TNBC) cells metastasize to other organs. The study, published in Cancer Research, a journal of the American Association for Cancer Research, found these interactions both in animal models and human samples of TNBC.

“The studies we have conducted in the past decade on the microenvironment of triple-negative breast cancer have shown that not every TNBC tumor is the same,” said corresponding author Dr. Xiang Zhang, professor and William T. Butler, M.D., Endowed Chair for Distinguished Faculty in molecular and cellular biology and director of the Lester and Sue Smith Breast Center at Baylor. “Each tumor 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 grow, spread and resist therapies.”

In a previous work, the researchers studied the role of macrophages in TNBC resistance to therapy. In the current study, the team focused on the interactions between neutrophils, specifically those expressing high levels of the protein ICAM1 (ICAM1-high), and TNBC cells and how this affected tumor behavior.

Traditionally, scientists have thought that there are two types of neutrophils, one that helps tumors grow and another type that fights them,” said first author Dr. Ling Wu, postdoctoral associate in the Zhang lab. “We found that this does not seem to be the case. Our findings show that the same neutrophil may have different effects depending on the type of cancer cells they encounter.”

Not all TNBC cells in a tumor look and behave the same way. Some retain characteristics of epithelial cells while others keep characteristics of mesenchymal cells.

“We found that ICAM1-high neutrophils help epithelial-like cancer cells grow, survive and spread to other tissues by forming a mutually beneficial relationship,” Wu said. “On the other hand, the same ICAM1-high neutrophils attack and kill mesenchymal-like cancer cells.”

When neutrophils interact with epithelial-like cancer cells, the relationship becomes cooperative. Neutrophils bind tightly to these cancer cells through adhesion molecules like F11R. Neutrophils naturally tend to leave the tumor microenvironment, crossing back into the blood circulation. When they leave the tumor, they carry the tumor cells with them, helping the cancer spread to other organs.

“At the same time, we observed that neutrophils bound to epithelial-like TNBC cells live longer than non-associated neutrophils – both cancer cells and neutrophils help each other,” Wu said. “Over time, this interaction can shape the composition of the tumor, favoring cancer cells that cooperate with neutrophils and creating distinct tumor environments.”

“We also looked at human triple-negative breast cancer samples and found similar results, supporting the idea that ICAM1-high neutrophils help cancer cells enter the bloodstream,” said Zhang, who is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Tumors with more ICAM1-high neutrophils were associated with poorer patient outcomes. Taken all together, our findings suggests that the tumor microenvironment is like a natural ecosystem in which the different components interact and affect each other, shaping the ecosystem’s evolution toward survival.”

Other contributors to this work include Zhan Xu, Jun Wang, Fengshuo Liu, Yunfeng Ding, Yang Gao, Siyue Wang1, Jun Liu, Hilda L. Chan1, Weiguo Wu, Yi-Hsuan Wu, Liqun Yu, Xiaoxin Hao, Xuan Li, David G. Edwards, Cher Sha1, Tobie D. Lee, Nan Guan, Sergio Aguirre, Luis Becerra-Dominguez, Dane Hoffman, Xiang Chen, Charlotte Helena Rivas, Xiaoyuan G. Yan, Igor L. Bado, Weijie Zhang, Qian Zhu, Arun Sreekumar and Robert L. Satcher. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Ohio State University, the Awty International School – Houston, Icahn School of Medicine, Mount Sinai Tisch Cancer Center and the University of Texas MD Anderson Cancer Center at Houston.

This study was supported by the U.S. Department of Defense (grant DAMD HT9425-23-1-0493), National Cancer Institute grants (CA183878, CA251950, CA221946, CA227904, CA253533 and P50CA186784) and the Breast Cancer Research Foundation. Further support was provided by National Institutes of Health grants (S10OD023469, S10OD025240, S10-OD032185, R00CA279899, CA125123 and RR024574), P30EY002520 and Cancer Prevention and Research Institute of Texas grants (RP200504 and RP180672).