A carregar...
Publicação
Unveiling the clinical relevance of low density neutrophils in Breast Cancer patients
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 2.9 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
Neutrophils are prominent immune components of solid tumors, which can protect against the onset
of cancer (N1) or have protumor activity (N2). Circulating neutrophils, divided into high density
neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells,
respectively. LDN, practically absent in non-pathological conditions, have been extensively studied
in cancer, due to their increased frequency in this disease and their protumor phenotype. However,
this has been mainly demonstrated in animal models and proper validation in humans is an urgent
need. In this thesis, we enlightened the clinical impact of LDN in breast cancer (BC) patients. We
observed that LDN were practically absent in healthy donors’ blood, while significantly increased in
the blood of 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 in patients with good response. The association of a higher incidence of
circulating LDN and the worse prognosis of BC patients could be explained by the protumor features
exhibited by these cells. Namely, there are more LDN expressing the immunosuppressive markers
PD-L1 and CCR4, than HDN. Additionally, LDN also showed increased expression of activation
markers; robust formation of neutrophil extracellular traps; augmented phagocytic activity and
higher capacity to release reactive oxygen species, which altogether contribute for tumor
development and metastization. Moreover, the percentage of LDN in BC patients’ blood was
positively correlated with the immunosuppressive CCR4+ regulatory T cells and negatively
correlated with activated cytotoxic T lymphocytes, corroborating the impairment on the antitumor
immune responses by LDN, which was further demonstrated ex vivo. Hence, this thesis reveals the
potential of LDN as a clinical meaningful biomarker of BC response to treatment and opens new
avenues for developing targeted immunotherapies.
Descrição
Palavras-chave
Low density neutrophils Breast cancer Biomarker Neoadjuvant chemotherapy