Fluorescence microcopy image of gamma delta T cells (green) attacking cancer cells (blue). To get tot he cancer cells, the immune cells need to navigate through a dense extracellular matrix that surrounds the tumor tissue (red).
The mandala artistically represents the research findings: The colorful circle represents a breast cancer stem cell (BCSC) whose surface structures can be recognized and killed by gamma delta T cells. The grey patterns illustrate BCBCs that have concerted differentiation and immune escape, remaining invisible to the immune cells.
Newswise — TNBC is a lethal type of breast cancer that is highly aggressive and difficult to treat. It has a high likelihood of recurrence due to the presence of breast cancer stem cells, which drive tumor growth and relapse. To improve therapy for TNBC, it is necessary to eliminate these tough cells. Researchers from the University of Freiburg found that breast cancer stem cells become invisible to the immune system through coordinated differentiation and metabolic changes. The drug zolendronate could counteract this metabolic change and make immunotherapy with gamma delta T cells more effective against TNBC. The study was led by Prof. Dr. Susana Minguet from the Cluster of Excellence CIBSS at the University of Freiburg, in collaboration with Dr. Jochen Maurer, Dr. Mahima Swamy, and collaborators from the University Hospital Freiburg. It was published in Cancer Immunology Research, a journal of the American Association for Cancer Research.
TNBC cells hide from gamma delta T cell
Gamma delta T cells are unique in their ability to identify and destroy cells that produce stress-induced molecules and phosphoantigens, which are common characteristics of cancer cells. Due to their distinct mode of action, gamma delta T cells are being explored as a potential alternative to current immunotherapies. In this study, the researchers evaluated the impact of gamma delta T cells on TNBC using both isolated cancer cells and a newly developed mouse model that mimics the tumor characteristics observed in human patients.
Although gamma delta T cells showed effectiveness against isolated breast cancer stem cells from patients, their efficacy was significantly reduced in the mouse model due to adaptations made by the cancer cells to evade detection by the immune system. The researchers discovered that these adaptations included the downregulation of the mevalonate pathway, a metabolic pathway that produces phosphoantigens – one of the molecules recognized by gamma delta T cells. This evasion mechanism is likely present in TNBC patients as well, as analysis of public patient databases revealed that decreased expression of critical molecules in the mevalonate pathway is associated with a poorer prognosis.
The immune evasion of TNBC cells is reversible
Fortunately, the newly discovered immune evasion mechanism can be countered using the FDA-approved drug zolendronate, which is commonly prescribed for the treatment of osteoporosis and bone metastasis. In the study, treatment with zolendronate made gamma delta T cells much more effective in eliminating the escaped cancer cells. "Our results help explain why current clinical trials using gamma delta T cells have not yielded the expected outcomes," explains Minguet. "We have identified a potential pharmacological strategy to reverse immune evasion, opening up possibilities for new combination immunotherapies for triple-negative breast cancer."
Factual overview
- Original publication: Katrin Raute, Juliane Strietz, Maria Alejandra Parigiani, Geoffroy Andrieux, Oliver S. Thomas, Klaus M. Kistner, Marina Zintchenko, Peter Aichele, Maike Hofmann, Houjiang Zhou, Wilfried Weber, Melanie Boerries, Mahima Swamy, Jochen Maurer, Susana Minguet (2023): Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands. In: Cancer Immunology Research.
https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-22-0296
- Susana Minguet has been recently appointed as Heisenberg Professor at the Faculty of Biology of the University of Freiburg and is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies and of BIOSS – Centre for Biological Signalling Studies. Her work focuses on gaining a better understanding of the molecular mechanisms that lead to the activation of B and T lymphocytes.
https://www.bioss.uni-freiburg.de/groups/minguet-group/home/
- The study was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG (CIBSS - EXC 2189, CRC-1479, and FOR-2799) and the German Federal Ministry of Education and Research.
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Credit: Katrin Raute / University of Freiburg
Caption: Fluorescence microcopy image of gamma delta T cells (green) attacking cancer cells (blue). To get tot he cancer cells, the immune cells need to navigate through a dense extracellular matrix that surrounds the tumor tissue (red).
Credit: Susana Minguet / CIBSS, BIOSS, University of Freiburg
Caption: The mandala artistically represents the research findings: The colorful circle represents a breast cancer stem cell (BCSC) whose surface structures can be recognized and killed by gamma delta T cells. The grey patterns illustrate BCBCs that have concerted differentiation and immune escape, remaining invisible to the immune cells.
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