{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T06:57:24Z","timestamp":1774767444560,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011733","name":"Liga Portuguesa Contra o Cancro","doi-asserted-by":"publisher","award":["Terry Fox Research Grant 2019"],"award-info":[{"award-number":["Terry Fox Research Grant 2019"]}],"id":[{"id":"10.13039\/501100011733","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Consortium Tagus Tank","award":["Clinical Research Prize 2018"],"award-info":[{"award-number":["Clinical Research Prize 2018"]}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/114023\/2015"],"award-info":[{"award-number":["PD\/BD\/114023\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/148422\/2019"],"award-info":[{"award-number":["SFRH\/BD\/148422\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"iNOVA4Health","award":["UIDB\/04462\/2020"],"award-info":[{"award-number":["UIDB\/04462\/2020"]}]},{"name":"iNOVA4Health","award":["DAI\/2019\/46"],"award-info":[{"award-number":["DAI\/2019\/46"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers13153841","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"3841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"Diana P.","family":"Saraiva","sequence":"first","affiliation":[{"name":"iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-4987","authenticated-orcid":false,"given":"Sofia","family":"Azeredo-Lopes","sequence":"additional","affiliation":[{"name":"Public Health and Biostatistics Department, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]},{"given":"Ana","family":"Antunes","sequence":"additional","affiliation":[{"name":"CHRC, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]},{"given":"Rute","family":"Salvador","sequence":"additional","affiliation":[{"name":"iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]},{"given":"Paula","family":"Borralho","sequence":"additional","affiliation":[{"name":"Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal"},{"name":"Instituto de Anatomia Patol\u00f3gica, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"given":"Beatriz","family":"Assis","sequence":"additional","affiliation":[{"name":"Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal"}]},{"given":"Isabel L.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal"}]},{"given":"Zita","family":"Seabra","sequence":"additional","affiliation":[{"name":"Unidade de Imagiologia, Hospital Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal"}]},{"given":"Ida","family":"Negreiros","sequence":"additional","affiliation":[{"name":"Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal"}]},{"given":"Ant\u00f3nio","family":"Jacinto","sequence":"additional","affiliation":[{"name":"iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]},{"given":"Sofia","family":"Braga","sequence":"additional","affiliation":[{"name":"iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"},{"name":"Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9016-9173","authenticated-orcid":false,"given":"M. Guadalupe","family":"Cabral","sequence":"additional","affiliation":[{"name":"iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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