New Targets for Treatment of Triple-Negative Breast Cancer Discovered

Four new subtypes of cells within triple-negative breast cancer (TNBC) have been uncovered, containing promising new therapeutic targets for the disease, according to an article published in EMBO Journal.^1,2

Researchers from the Garvan Institute of Medical Research demonstrated that 1 of the new subtypes of cells is able to produce molecules that suppress immune cells, which allows cancer cells to evade the immune system. This understanding may progress research so that a new class of therapies for TNBC can be developed.^1,2

"Patients with triple-negative breast cancers have a poor prognosis, in large part because treatment approaches have advanced very slowly," said senior author of the study Alex Swarbrick, head of the Tumour Progression Laboratory at Garvan Institute, in a press release. "We've analyzed individual cells in patient tumor samples to gain unprecedented insights into what makes up a tumor, allowing us to identify subtypes of cells and investigate their role in disease."²

TNBC is named as such because it lacks 3 receptors for oestrogen, progesterone, and the human epidermal growth factor receptor 2 (HER2) protein. These 3 receptors are targeted with specialized therapies in other breast cancers, but by their nature, such therapies are ineffective for TNBC.^1,2

For this reason, patients with TNBC lack treatment options and experience poor outcomes. A significant number of these patients die within 5 years of diagnosis.^1,2

"In our study, we searched for new potential targets for therapy by analyzing the individual cells inside triple-negative breast tumors. This includes not only the cancer cells themselves, but also the surrounding host cells, such as immune and connective tissue cells, which can be thought of as the cancer 'ecosystem' that supports a tumor to grow and spread," said Sunny Wu, PhD, first author of the study, in a press release.²

In order to create a snapshot of each cell's gene activity, the researchers used 24,271 individual cells extracted from biopsy samples of 5 patients with TNBC for next-generation sequencing. Through this analysis, the researchers were able to detect more than 6000 unique ribonucleic acid (RNA) molecules in every cell.^1,2

The researchers observed 4 cell subtypes of stromal cells that form the connective tissues, although prior research on the subject had only considered the presence of 1 type of stromal cell.^1,2

With the role of the additional cell subtypes in TNBC unknown, the researchers investigated further to reveal some surprising interactions among the signaling molecules produced by the stromal cells and immune cells.^1,2

"Our findings suggest that there is significant crosstalk between the immune system and stromal cells, which were generally thought to have only a structural role in cancers," Swarbrick said in the press release.²

For example, the researchers discovered that 1 cell subtype, the inflammatory cancer-associated fibroblasts (iCAFs), released the chemokine CXCL12, which is a signaling molecule that suppresses T cells’ anti-tumor activity.^1,2

"This is significant because immunotherapy—which is designed to activate the patient's immune system against a tumor—has limited response in many patients with triple-negative breast cancer," Swarbrick said in the press release. "If iCAFs are suppressing T cells in triple-negative breast cancer, and we can remove this interaction, T cells will be more susceptible to activation and more likely to attack the cancer."²

For this reason, combining immunotherapy with a treatment that stops the interaction between stromal cells and immune cells may lead to improving the treatment of TNBC, according to the researchers.^1,2

The team explained that to investigate this issue further, they will analyze more breast cancer samples in order to more thoroughly understand the cells that comprise TNBC, their interactions, and interventions to stop disease progression.^1,2

"Pathologists have been describing cancers under the microscope for more than 150 years, but we still only have a shallow understanding of the cells that are there," Swarbrick said in the press release. "Cellular genomics is showing us that what we once thought of as one cell type is in reality a diversity of cell types, which will have a significant impact on how we tailor treatments in future."²

REFERENCE

• Wu S, Roden D, Wang C, et al. Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer. EMBO Journal. 2020; e104063. doi: 10.15252/embj.2019104063.
• Breast cancer 'ecosystem' reveals possible new targets for treatment. Garvan Institute of Medical Research; August 13, 2020. eurekalert.org/pub_releases/2020-08/giom-bc080920.php. Accessed on August 17, 2020.