Research Papers:

Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses

Diana P. Saraiva, Bruna F. Correia, Rute Salvador, Nídia de Sousa, António Jacinto, Sofia Braga and M. Guadalupe Cabral _

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Oncotarget. 2021; 12:2388-2403. https://doi.org/10.18632/oncotarget.28135

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Diana P. Saraiva1,*, Bruna F. Correia1,*, Rute Salvador1, Nídia de Sousa1, António Jacinto1, Sofia Braga1,2 and M. Guadalupe Cabral1

1 iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, Lisbon, Portugal

2 Instituto CUF de Oncologia, Lisbon, Portugal

* These authors contributed equally to this work

Correspondence to:

M. Guadalupe Cabral, email: [email protected]

Keywords: breast cancer; chemotherapy response; tumor-associated neutrophils; low density neutrophils; biomarker

Received: July 29, 2021     Accepted: November 10, 2021     Published: November 23, 2021

Copyright: © 2021 Saraiva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Neutrophils are prominent immune components of tumors, having either anti-tumor (N1) or pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN are rare in non-pathological conditions, but frequent in cancer, exhibiting a pro-tumor phenotype. These findings have been mainly demonstrated in animal models, thus proper validation in humans is still imperative. Here, we observed that LDN were increased in the blood of breast cancer (BC) patients, particularly with metastatic disease. Within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than patients with a good response. The higher incidence of LDN in BC patients with severe disease or resistance to treatment can be explained by their pro-tumor/immunosuppressive characteristics. Moreover, the percentage of LDN in BC patients’ blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with immunosuppressive regulatory T cells. The ability of LDN to spoil anti-tumor immune responses was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a biomarker of BC response to treatment and opens new avenues for developing new immunotherapies.

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