Abstract

Background

In breast cancer, patients who develop stage IV metastatic disease have a median survival rate of 15%. Understanding the cellular mechanisms underpinning the progression of metastatic disease may present novel therapeutic interventions. In cancer, subsets of γδ T cells have been shown to present as anti-tumorigenic and pro-tumorigenic. In the K14-Cre;Cdh1^F/F;Trp53^F/F (KEP) model of breast cancer, IL-17-producing γδ T cells promote lung metastasis by expanding neutrophils to suppress anti-tumorigenic CD8⁺ T cells. Selectively targeting IL-17-secreting γδ T cells in breast cancer metastasis may have therapeutic potential.

Method

To investigate which molecules govern the activation of pro-tumorigenic γδ T cells, we measured the expression of various activating receptors on CD27⁺ and CD27^— γδ  T cells from tumour naïve or tumour-bearing mice, as CD27 stratifies IFNγ-producing (CD27⁺) from IL-17-producing (CD27^—) γδ T cells.

Results

Surprisingly, we found that expression of NKG2D, a receptor involved in recognition of stressed or malignantly transformed cells is higher on CD27^—  γδ T cells compared with CD27⁺ cells. This increased expression of NKG2D on CD27^— γδ T cells was specific, as other cytotoxic receptors were elevated on CD27⁺ γδ T cells.  Furthermore, in the K14-Cre;Brca1^F/F;Trp53^F/F (KB1P) model of breast cancer, we found that NKG2D ligands are upregulated in the myeloid compartment at metastatic sites, such as the lung of tumour-bearing mice.

Conclusion

We are currently investigating the interplay between these NKG2D ligand-expressing myeloid cells and IL-17-producing γδ T cells to determine whether the NKG2D axis plays a role in breast cancer metastasis.