Triple negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high chance of recurrence. Tumor growth and TNBC relapse are driven by breast cancer stem cells, and improved therapies that can eliminate those resistant cells are urgently needed. Researchers at the University of Frieburg discovered that the coordinated differentiation and changes in metabolism of breast cancer stem cells make them invisible to the immune system. Counteracting the metabolic change with the drug zolendronate could make gamma delta T-cell immunotherapy more effective against TNBC. The research team was led by Prof. Dr. Susana Minguet from the CIBSS Cluster of Excellence – Center for Integrative Studies of Biological Signaling at the University of Freiburg, in collaboration with Dr. Jochen Maurer from the RWTH Aachen University Hospital, Dr. Mahima Swamy from the University of Dundee/Scotland and collaborators from the University Hospital Freiburg. The study was published in the Journal cancer Immunology Research, a journal of the American Association for Cancer Research.
TNBC cells hide from gamma delta T cells
Gamma delta T cells recognize and kill cells that produce stress-induced molecules and phosphoantigens, a common feature of cancer cells. Because gamma delta T cells work differently than 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 newly developed mouse model that closely replicates tumor properties found in human patients.
While gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations in cancer cells that allowed them to go undetected by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens, one of the classes of molecules recognized by gamma T cells. It is likely that this escape mechanism also occurs in patients with TNBC: analysis of public patient databases showed that reduced expression of key mevalonate pathway molecules correlates with poorer prognosis.
Immune evasion of TNBC cells is reversible
This newly discovered escape mechanism can be countered with the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escape cells with zolendronate, the gamma T cells became much more efficient at killing off the cancer. “Our findings explain why current clinical trials using gamma delta T cells are not having the expected success,” summarizes Minguet. “We found a potential pharmacological approach to reverse immune escape, paving the way for new combinatorial immunotherapies for triple-negative breast cancer.”
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