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Methylselenol producing selenocompounds enhance the efficiency of mammaglobin-A peptide vaccination against breast cancer cells.

ABSTRACT: Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP-1 cells, an apparent proficient antigen that presents a human monocyte-like cell line, and their eventual activation of MamA2.1 (HLA-A2 immunodominant epitope of Mam-A) specific cytotoxic CD8+ T lymphocytes (CTLs). The results revealed that, following treatment with methylselenol producing compounds [methylselenic acid (MSA) and dimethylselenide (DMDSe)], the expression of HLA class-I was increased and components involved with the antigen presentation machinery of THP-1 cells were upregulated. Furthermore, CTLs activated by MamA2.1 peptide presenting THP-1 cells, pre-treated with MSA and DMDSe, demonstrated an enhanced cytotoxicity in HLA-A2+/Mam-A+ AU565 and UACC-812 breast cancer cell lines when compared with CTLs activated by THP-1 cells without drug treatment. However, no significant cytotoxicity was observed under similar conditions in HLA-A2+/Mam-A- MCF-7 and MDA-MB-231 breast cancer cell lines. The results indicated that treatment with methylselenol producing compounds retained antigen-dependent activation of CD8+ T cells. The data of the current study demonstrated that MSA and DMDSe potentiated effector cytotoxic responses following TAA specific activation of CTLs, indicating their future role as vaccine adjuvants in cancer immunotherapy.

SUBMITTER: Babaer D

PROVIDER: S-EPMC6876340 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Methylselenol producing selenocompounds enhance the efficiency of mammaglobin-A peptide vaccination against breast cancer cells.

Babaer Duaa D Zheng Mu M Ivy Michael T MT Zent Roy R Tiriveedhi Venkataswarup V

Oncology letters 20191018 6

Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules ...[more]

PMID: 31807192

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Project description:Aromatase inhibitors (AIs), such as letrozole, are considered as first-line treatment for estrogen receptor-positive breast cancer in postmenopausal women. Despite the successful use of letrozole, resistance to therapy, tumor relapse and metastasis remain principal causes of patient mortality. Although there is no therapy currently available for AI-resistant breast cancer, previous reports have demonstrated that AI resistance is associated with hormone independence, increased growth factor signaling, enhanced cellular motility and epithelial to mesenchymal transition (EMT). This suggests a convergence of EMT and cancer stem cells (CSCs) in endocrine resistance. The present study evaluated the contribution of mammospheres in letrozole-resistant breast cancer by characterizing mammospheres and their potential impact on cellular motility. Ovariectomized immunocompromised female mice were inoculated in the mammary fat pad with either letrozole-resistant MCF-7 cells (LTLT-Ca) or letrozole-sensitive MCF-7 cells (AC-1). Subsequently, intratumoral CSC marker expression was assessed by immunohistochemistry. The results indicated that LTLT-Ca tumors were CD44+/CD24+, while AC-1 tumors presented low CD44/CD24 expression. Since mammosphere formation depends on CSCs, both cell lines were cultured either adherently (2D) or as mammospheres (3D) to assess the CD44/CD24 protein expression profile. When 3D culturing both cell lines, higher expression levels of CD44 and CD24 were observed when compared with their adherent counterparts, with the most robust change observed in the LTLT-Ca cell line. To quantitate the breast cancer stem cell activity, mammosphere formation assays were performed, and the LTLT-Ca cells formed mammospheres at a 3.4-fold higher index compared with AC-1 cells. Additionally, targeted gene expression arrays were conducted to compare the LTLT-Ca 3D and 2D cells, revealing that LTLT-Ca 3D cells displayed decreased expression levels of genes involved in cell adhesion and tumor suppression (e. g., E-cadherin, caveolin 1 and β-catenin). To validate this finding, wound healing assays were performed, and LTLT-Ca mammospheres exhibited a 70% wound closure, whereas AC-1 mammospheres exhibited a 39% wound closure. Collectively, the present findings demonstrated a strong association between AI-resistant mammospheres and an increased propensity for migration, which may be indicative of a poor prognosis.

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Methylselenol producing selenocompounds enhance the efficiency of mammaglobin-A peptide vaccination against breast cancer cells.

Publications

Methylselenol producing selenocompounds enhance the efficiency of mammaglobin-A peptide vaccination against breast cancer cells.

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