Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes

Ramessur, A.; Ambasager, B.; Aramburu, I. V.; Peakman, F.; Gleason, K.; Lehmann, C.; Papayannopoulos, V.; Coombes, C.; Malanchi, I.

doi:10.1101/2023.04.19.537022

bioRxiv · 10.1101/2023.04.19.537022

Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes

Ramessur, A.·Ambasager, B.·Aramburu, I. V.·Peakman, F.·Gleason, K.·Lehmann, C.·Papayannopoulos, V.·Coombes, C.·Malanchi, I.

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Abstract

PurposeA high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear. Patients and MethodsHere, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases. ResultsWe found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype. ConclusionsOur results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation. Clinical RelevanceThe current study aims to investigate cancer-specific changes in circulating neutrophils in patients with newly diagnosed early breast cancer before any therapeutic intervention. We found L-selectin (CD62L) changes in circulating neutrophils from patients with early-stage breast cancer compared to healthy volunteers, which is an indication of an early phenotypical change. Moreover, these changes in CD62L were dependent on the breast cancer sub-type, showing opposing trends according to the hormonal receptor status of the tumour. Importantly, this subtype dependent phenotypic alteration was reflected in broader intracellular signalling perturbation when measuring intracellular kinase activity. Moreover, those cancer perturbed neutrophils, show expanded life span when cultured ex vivo, suggesting an alteration in their physiologic state. The tumour-specific kinase activation patterns in circulating neutrophils may be useful in conjunction with other markers to distinguish patients with cancer from those with benign lesions of the breast.

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Ramessur, A., Ambasager, B., Aramburu, I. V., Peakman, F., Gleason, K., Lehmann, C., Papayannopoulos, V., Coombes, C., Malanchi, I.. 2023-04-21. Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes. https://doi.org/10.1101/2023.04.19.537022

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