Gamma delta T cells can fight aggressive breast cancer

Researchers in Germany have discovered the mechanism by which cancer cells escape the immune system – and how to reverse it.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal form of breast cancer, with limited treatment options and a high chance of recurrence. TNBC tumor growth and recurrence are driven by breast cancer stem cells, and better therapies that can remove these tough cells are urgently needed.

Researchers from the University of Frieburg in Germany found that the coordinated differentiation and metabolic changes of breast cancer stem cells make them invisible to the immune system. Counteracting metabolic changes with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC.

The research team was led by Susana Minguet from the CIBSS Cluster of Excellence – Center for Integrative Biological Signaling Studies at the University of Freiburg, in collaboration with Jochen Maurer from University Hospital RWTH Aachen, Mahima Swamy from the University of Dundee, Scotland, and collaborators from University Hospital Freiburg. This study is published in the journal Cancer Immunology Research.

TNBC cells hide from gamma delta T cells

Gamma delta T cells recognize and kill cells that produce stress-induced molecules and phosphoantigens, common characteristics of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that mimics the tumor properties found in human patients.

While gamma delta T cells performed well against breast cancer stem cells isolated from patients, they had a much weaker effect in mouse models. This is due to adaptations of cancer cells that allow them to remain unnoticed by the immune system, the researchers found. These adaptations include downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens – a class of molecules recognized by gamma T cells. This mechanism of escape is most likely also present in patients with TNBC: analysis of public patient databases shows that reduced expression of a key molecule of the mevalonate pathway correlates with a poorer prognosis.

Evasion of TNBC cell immunity is reversible

This newly discovered escape mechanism can be countered by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastases. When the researchers treated the escape cells with zolendronate, the gamma T cells became much more efficient at clearing the cancer.

“Our findings explain why current clinical trials using gamma delta T cells have not yielded the hoped-for success,” said Minguet.

“We discovered the possibility of a pharmacologically based approach to restore immune escape, which paved the way for a new combinatorial immunotherapy for triple negative breast cancer.”