Immunosuppressive profiles in liquid biopsy at diagnosis predict response to neoadjuvant chemotherapy in triple-negative breast cancer.
Eur J Cancer
; 139: 119-134, 2020 11.
Article
in En
| MEDLINE
| ID: mdl-32987253
ABSTRACT
BACKGROUND:
Triple-negative breast cancer (TNBC) is characterised by high pathological complete response to neoadjuvant chemotherapy (NAC). However, refractory and poor NAC responders still face very poor outcome, emphasising the urgent need for tools that facilitate identification of these patients, so that surgery or alternatives to NAC are considered early in the treatment protocol. MATERIALS ANDMETHODS:
We combined metabolomics, exosome circulating miRNAs and flow cytometry experimental approaches in TNBC patients at diagnosis with immunohistochemistry in needle biopsy tumours to generate NAC-response predictive models. We also co-cultured and studied crosstalk between isolated patient-derived early myeloid-derived suppressor cells (eMDSCs) and TNBC cancer cell lines.RESULTS:
Blood-derived liquid biopsy biomarkers display a novel immunosuppressive profile of tryptophan-derived metabolites and eMDSC levels that significantly predict NAC response. Notably, indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumour cells inversely correlated with circulating tryptophan levels but directly correlated with the level of eMDSCs. In addition, a set of circulating exosome miRNAs that target pathways of immune maturation also predicted poor NAC response prior to chemotherapy. Interestingly, expression of IDO1 increased when TNBC cell lines were co-cultured with patient-derived eMDSCs and this, in turn, promoted proliferation of eMDSCs.CONCLUSION:
Our findings demonstrate that the suppressive pathways of the immune system play a key role in modulating the NAC response in TNBC. We identify a crosstalk mechanism between tumour cells and eMDSCs that exacerbates immunosuppression. These results provide a potential new tool to identify poor NAC responders for alternative strategies of treatment, including early surgical resection of the tumour, and to explore in them alternative immune therapies.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triple Negative Breast Neoplasms
/
Immune Tolerance
Type of study:
Diagnostic_studies
/
Guideline
/
Observational_studies
/
Prognostic_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Middle aged
Language:
En
Journal:
Eur J Cancer
Year:
2020
Document type:
Article
Affiliation country:
Spain
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM