TY - JOUR
T1 - Expression of hla-dr in cytotoxic t lymphocytes
T2 - A validated predictive biomarker and a potential therapeutic strategy in breast cancer
AU - Saraiva, Diana P.
AU - Azeredo-Lopes, Sofia
AU - Antunes, Ana
AU - Salvador, Rute
AU - Borralho, Paula
AU - Assis, Beatriz
AU - Pereira, Isabel L.
AU - Seabra, Zita
AU - Negreiros, Ida
AU - Jacinto, António
AU - Braga, Sofia
AU - Cabral, M. Guadalupe
N1 - Funding Information:
Funding: This work was supported by Terry Fox Research Grant 2019 from Liga Portuguesa Contra o Cancro; Clinical Research Prize 2018 from Consortium Tagus Tank; Fundação para a Ciência e Tecnologia (PD/BD/114023/2015 for DPS and SFRH/BD/148422/2019 for RS) and iNOVA4Health (UIDB/04462/2020, DAI/2019/46).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.
AB - Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.
KW - 3D co-cultures
KW - Biomarker
KW - Breast cancer
KW - Cytotoxic T lymphocytes
KW - HLA-DR
KW - Immune-modulation
KW - Neoadjuvant chemotherapy
UR - http://www.scopus.com/inward/record.url?scp=85111355049&partnerID=8YFLogxK
U2 - 10.3390/cancers13153841
DO - 10.3390/cancers13153841
M3 - Article
AN - SCOPUS:85111355049
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 15
M1 - 3841
ER -
