Gamma Delta T Cells Can Fight Against TNBC

Triple-negative breast cancer (TNBC) is the most aggressive and lethal type of breast cancer, with few treatment choices and a high risk of recurrence. Breast cancer stem cells cause tumor growth and relapse in TNBC, and better medicines that can eradicate these resilient cells are desperately needed.
The University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells render them immune-invisible. Counteracting the metabolic shift with the medication zolendronate may improve the efficacy of gamma delta T cell immunotherapy against TNBC.

Prof. Dr. Susana Minguet from the University of Freiburg’s Cluster of Excellence CIBSS—Center for Integrative Biological Signaling Studies led the research team, which included Dr. Jochen Maurer from the University Hospital RWTH Aachen, Dr. Mahima Swamy from the University of Dundee/Scotland, and collaborators from the University Hospital Freiburg. The findings were published in Cancer Immunology Research.

Gamma delta T cells identify and kill cells that release stress-induced chemicals and phosphoantigens, which are frequent in cancer cells. Because gamma delta T cells function differently than other types of T cells, they are being studied as an alternative to currently available immunotherapies. The current study used isolated cancer cells and a recently established mouse model that closely matches the tumor features reported in human patients to investigate the effect of gamma delta T cells on TNBC.

While gamma delta T cells were effective against isolated breast cancer stem cells from patients, their effect in the mouse model was much weaker. According to the researchers, this was owing to cancer cells’ modifications that allowed them to go undetected by the immune system.

Downregulation of the so-called mevalonate pathway, a metabolic process that leads to the synthesis of phosphoantigens, one of the types of molecules recognized by gamma T cells, was among these modifications. This escape strategy is likely to occur in TNBC patients as well: an investigation of public patient databases revealed that decreased expression of key molecules in the mevalonate pathway correlates with a poor prognosis.
The medicine zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastases, can block this newly found escape pathway. When the researchers gave the escapist cells zolendronate, the gamma T cells became far more effective in clearing the cancer.

“Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success,” Minguet says. We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer.”

Source Link