Regulation of IL-17-producing γδ T cells in breast cancer metastasis.


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Sarah C. Edwards1,Anna Kilbey2,Robert Wiesheu2,Erin R. Morris3,Liam Hayman2,Damiano Rami2,Seth B. Coffelt2
1Beatson CRUK,2Beatson CRUK. Institute of Cancer Sciences, University of Glasgow.,3Baker University, Baldwin City, Kansas

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;Cdh1F/F;Trp53F/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;Brca1F/F;Trp53F/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.