scholarly journals Determination of HLA-DR level in cytotoxic T lymphocytes: a new validated tool to predict breast cancer response to treatment

2021 ◽  
Author(s):  
Diana P Saraiva ◽  
Sofia Azeredo-Lopes ◽  
Ana Antunes ◽  
Rute Salvador ◽  
Paula Borralho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
Response To Treatment ◽  
Effective Response ◽  
Hla Dr ◽  
Therapeutic Decisions

Background: Neoadjuvant chemotherapy (NACT) is the usual treatment for locally-advanced breast cancer (BC). However, more than half of the patients lack an effective response to this treatment. Thus, it is urgent to find predictive biomarkers. Recently, we proposed the HLA-DR expression level in cytotoxic T lymphocytes (CTLs) as a robust biomarker to select, in advance, patients that will actually benefit from NACT. Patients and Methods: A total of 202 BC patients, 102 of which submitted to NACT, were enrolled in this study. 61 biopsies and 41 blood samples collected pre-NACT and 100 non-NACT tumor samples were immunophenotyped by flow cytometry. Both NACT and non-NACT patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. Results: Here we confirmed that HLA-DR level in CTLs is a highly sensitive and specific biomarker to predict BC response to NACT, reflected in circulation and independent of the patients age, BC subtype and other tumor-immunological features. Therefore, we developed a predictive probability model, based on the determination of HLA-DR level in tumor-infiltrating CTLs, that could be used to guide therapeutic decisions. Interestingly, this biomarker was also associated with progression-free survival, regardless the treatment. Contrary to HLA-DRnegative CTLs, HLA-DR+ CTLs were able to reduce the viability of tumor cells, in culture, in agreement with their higher expression of activation, proliferation and cytotoxicity-related molecules. Tissue-residency and memory markers were also increased in HLA-DR+ CTLs. These anti-tumor features of HLA-DR+ CTLs may justify the clinical observations. Conclusion: HLA-DR level in CTLs is a validated and independent biomarker to predict response to NACT which allow the establishment of a clinical meaningful tool to select in advance patients that will truly benefit from this treatment. Intriguingly, it may be further used as a biomarker of BC patients general prognosis.

scholarly journals Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3841
Author(s):  
Diana P. Saraiva ◽  
Sofia Azeredo-Lopes ◽  
Ana Antunes ◽  
Rute Salvador ◽  
Paula Borralho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Ex Vivo ◽  
Probability Model ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Effective Response ◽  
Hla Dr ◽  
Potential Biomarker

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.

Therapeutic Efficacy of MUC1-Specific Cytotoxic T Lymphocytes and CD137 Co-Stimulation in a Spontaneous Breast Cancer Model

2004 ◽  
Vol 20 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Pinku Mukherjee ◽  
Teresa L. Tinder ◽  
Gargi D. Basu ◽  
Latha B. Pathangey ◽  
Lieping Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Therapeutic Efficacy ◽  
Cancer Model ◽  
Breast Cancer Model

scholarly journals Modulation of MUC1 mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes

2001 ◽  
Vol 84 (9) ◽  
pp. 1258-1264 ◽  
Author(s):  
K Kontani ◽  
O Taguchi ◽  
T Narita ◽  
M Izawa ◽  
N Hiraiwa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Cancer Cells ◽  
Cytotoxic T Lymphocytes ◽  
Breast Cancer Cells ◽  
Escape Mechanism ◽  
Muc1 Mucin

Anti-Tumor Activities of XBP1 Antigen-Specific Cytotoxic T Lymphocytes Are Enhanced By HDAC6 Inhibitor ACY241

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2143-2143
Author(s):  
Jooeun Bae ◽  
Matthew Ho ◽  
Brandon Nguyen ◽  
Arghya Ray ◽  
Dharminder Chauhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Board Of Directors ◽  
Cytotoxic T Lymphocytes ◽  
Cytokine Production ◽  
Suppressor Cells ◽  
Advisory Committees ◽  
Hdac6 Inhibitor ◽  
Equity Ownership

Abstract The effects of histone deacetylase (HDAC) inhibition on immune effector cells may have significant clinical implications; however, this has not yet been elucidated. The goal of this study was to investigate the immunomodulatory potential of the selective HDAC6 inhibitor ACY241 in combination with a cancer vaccine to enhance the efficacy of antigen-specific cytotoxic T lymphocytes (CTL) and the specific activities against tumor cells. Here, we report the effects of ACY241 treatment on antigen expression, immune activation, proliferation, and functional activities of XBP1 antigen-specific cytotoxic T lymphocytes (XBP1-CTL). The antigen-specific CTL were generated in vitro by repeated stimulation with novel immunogenic heteroclitic HLA-A2 XBP1 peptides (YISPWILAV, YLFPQLISV), as described previously by our group (Bae et al. Leukemia 2011; Bae et al. Oncoimmunology 2014l; Bae et al. Leukemia 2016). We found that treatment with ACY241 up-regulated key co-stimulatory (CD28, CD40L) and activation (CD38, CD69, CD137) molecules on XBP1-CTL, without inducing expression of co-inhibitory checkpoints (PD1, LAG3, CTLA4, VISTA). In addition, ACY241 increased the frequency of memory CTL subsets and enhanced their anti-tumor activities (cytotoxic activity, Th1-type cytokine production, CTL proliferation) against HLA-A2+ and XBP1+ multiple myeloma, breast cancer, and colon cancer cells. The XBP1-CTL responses were dramatically increased in combination with ACY241, including higher levels of tumor-specific CD107a up-regulation, perforin release, IFN-g/IL-2/TNF-a cytokine production and proliferation of the CD3+CD8+ T cells expressing CD28/CD38 in response to the specific XBP1 peptides. ACY241 also enhanced the expression of various tumor-associated antigens (XBP1, CD138, CS1, BCMA, CD44), MHC class I/II molecules, along with co-stimulatory B7 molecules (CD80, CD86) on HLA-A2+ myeloma (U266), breast cancer (MDA-MB231) and colon cancer (SW480) cell lines. Furthermore, in vitro ACY241 treatment consistently decreased the frequency of immune suppressor cells including myeloid-derived suppressor cells (CD14- CD15+/CD11b+ CD33+/HLA-DRlow) and regulatory T cells (CD25+ FOXP3+/CD3+ CD4+) in peripheral blood or bone marrow mononuclear cells from multiple myeloma patients in a dose-dependent manner. In conclusion, our data demonstrates the immunomodulatory effects of selective HDAC6 inhibition by ACY241 and supports its potential role for improving tumor-specific CTL function and tumor cell recognition when used in combination with antigen-specific cancer vaccine. Disclosures Bae: OncoPep Inc.: Consultancy, Equity Ownership. Chauhan:Stemline Therapeutics: Consultancy. Hideshima:Acetylon: Consultancy; C4 Therapeutics: Equity Ownership. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Anderson:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Dovitinib plus fulvestrant in postmenopausal endocrine resistant HER2-/ HR+ breast cancer: A phase II, randomized, placebo-controlled study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS651-TPS651
Author(s):  
Fabrice Andre ◽  
Patrick Neven ◽  
Antonino Musolino ◽  
Luciano Latini ◽  
Mario Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
Performance Status ◽  
Locally Advanced ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Controlled Study ◽  
Double Blind

TPS651 Background: Overcoming endocrine resistance (ER) is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer (BC). Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with ER. Up to 8% pts with HR+/ human epidermal growth factor receptor 2 negative (HER2–) BC have amplification of the FGFR1 gene. Dovitinib (DOV), a potent inhibitor of FGFR, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor demonstrated antitumor activity in heavily pretreated BC pts with FGF-pathway amplification (FGFR1, FGFR2, or FGF3). The objective of this study is to determine if DOV plus fulvestrant (FUL) can improve outcomes in postmenopausal pts with endocrine resistant HER2-/HR+ BC. Methods: This multicenter, randomized, double-blind, placebo-controlled, ph II trial (NCT01528345) will enroll postmenopausal pts with HER2–/HR+ locally advanced or metastatic BC (N=150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting. Pts will be randomized 1:1 (stratified by FGF amplification and presence of visceral disease) to receive intramuscular FUL (500 mg q4w [with an additional dose 2 weeks after the initial dose]) plus oral DOV (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Primary endpoint is progression free survival (investigator’s assessment; RECIST v1.1). Secondary endpoints include overall response rate (investigator’s assessment; RECIST v1.1), duration of response, overall survival, time to deterioration of ECOG performance status, pt-reported outcome scores over time, safety, and assessment of plasma pharmacokinetic concentrations of FUL and DOV. Additionally, the pharmacodynamic effect of DOV on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to DOV will be explored. As of 21 Jan 2013, 128 pts had molecular screening; 73 pts are enrolled (of these 9 pts are FGF amplified). Clinical trial information: NCT01528345.

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