Cancer Metabolism

Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer

Abstract

Background

Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cell subtypes, including the subsequent impact on patient outcome.

Methods

SLC1A5, SLC7A5, SLC3A2 and immune cell markers CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1, were assessed by using immunohistochemistry on TMAs constructed from a large BC cohort (n = 803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells.

Results

High SLCs were significantly associated with PDL1 and PD1 +, FOXP3 +, CD68 + and CD20 + cells (p < 0.001). Triple negative (TN), HER2 + and luminal B tumours showed variable associations between SLCs and immune cell types (p ≤ 0.04). The expression of SLCs and PDL1, PD1 +, FOXP3 + and CD68 + cells was associated with poor patient outcome (p < 0.001). Knockdown of SLC7A5 significantly reduced PDL1 expression.

Conclusion

This study provides data that altered glutamine pathways in BC that appears to play a role in deriving specific subtypes of immune cell infiltrates, which either support or counteract its progression.

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Acknowledgements

We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We thank the University of Nottingham (Nottingham Life Cycle 6 and Cancer Research Priority Area) for funding.

Author contributions

R.E. contributed to writing, IHC staining, scoring, data analysis and interpretation; M.L.C. contributed to writing and reviewing the paper; M.A. and L.A. contributed to analysis and reviewing the paper; I.O.E. and E.A.R. contributed to writing and reviewing the paper; A.R.G. contributed to study design, data analysis and interpretation, writing and reviewing the paper.

Author information

Correspondence to Andrew R. Green.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Nottingham Research Ethics Committee 2 under the title ‘Development of a molecular genetic classification of breast cancer’ and the North West–Greater Manchester Central Research Ethics Committee under the title ‘Nottingham Health Science Biobank (NHSB)’ reference number 15/NW/0685. The study was performed in accordance with the Declaration of Helsinki.

Funding

Sources of study funding are the University of Nottingham (Nottingham Life Cycle 6 and Cancer Research Priority Area).

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Not applicable.

Data availability

The data sets generated during this study are available from the corresponding author on reasonable request.

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Ansari, R.E., Craze, M.L., Althobiti, M. et al. Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer. Br J Cancer 122, 94–101 (2020). https://doi.org/10.1038/s41416-019-0626-z

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