Breast cancer stem cells (BCSC) play a key role in metastasis formation, tumor recurrence, and mortality of patients. Therapies directed against these cells are urgently needed specially in the treatment of more aggressive triple-negative breast cancer (TNBC) that is enriched in BCSC.
In a recent paper the authors investigate the potential use of gamma/delta T cells to treat breast cancer and especially TNBC. For that, they expanded gamma/delta T cells from peripheral blood mononuclear cells of healthy donors and tested their capacity to kill BCSC-derived cell lines in vitro.
Gamma/delta expanded cells were very active killing these BCSC-derived cell lines. The 90% of the gamma/delta population that they used was V gamma 9/ V delta 2. It is well known that these T cells are the main responsible of the response to phosphoantigens. Intracellular phosphoantigens on the target cell are key factors to activate V gamma 9/ V delta 2 T cells. Tumor phosphoantigens in the context of butyrophilins 3A1 and 2A1 can be recognized by the TCRs of V gamma 9/ V delta 2 T cells.
Then, they tried to get the same effect in vivo. For that, they analyzed the effect of gamma/delta T cell immunotherapy in a xenografted BCSC-derived tumor, but in this case, there was no response.
Analyzing in vitro the possible causes of this lack of response they found that the xenografted tumor cells were not stem cells as those that gave origin to the tumor but they became more differentiated cells. Due to that, tumor cells lacked some important molecules required for gamma delta activation and, beside that, had low levels of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. The level of phosphoantigens in these tumor cells depends on the activity of the HMGCR enzyme.
To explore this, they did cytotoxicity assays in the presence of zoledronate or mevastatin. Statins prevent bisphosphonate-induced gamma, delta-T-cell proliferation and activation in vitro. On the contrary, zoledronate, the only biphosphonate currently approved for the prevention and treatment of skeletal relevant events in patients with metastatic bone lesions, especially from advanced renal cell carcinoma, prostate cancer breast cancer, is an activator of V gamma 9/ V delta 2 T cells. The use of zoledronate in vitro made the xenograft tumor derived cells sensible again to gamma delta T cell-mediated killing. Thus, zoledronate avoided the gamma delta immune scape that xenograft tumor derived cells had in vivo.
Immunotherapy based on gamma/delta T cells (specially V gamma 9/ V delta 2) combined with zoledronate or a similar drug could be a future potential treatment for triple-negative breast cancer.
At Immunerepertoires, in our standard service, we include information about the usage of these V-J combinations and specifically look for data that could point to an expansion of this kind of gamma / delta T cells.
References:
https://pubmed.ncbi.nlm.nih.gov/37139603/
Picture:
Crystal structure PDB 8DFW