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A Potent CD1d-binding Glycolipid for iNKT-Cell-based Therapy Against Human Breast Cancer.

關, 壽之 東京慈恵会医科大学 DOI:info:doi/10.21873/anticanres.13147

2020.10.15

概要

Background/Aim: Invariant natural killer T-cells (iNKT) stimulated by CD1d-binding glycolipids have been shown to exert antitumor effects by a number of studies in a mouse model. Breast cancer is a devastating disease, with different types of breast cancer recurring locally or distant as metastatic/advanced disease following initial treatment. The aim of this study was to examine the tumoricidal effect of a CD1d- binding glycolipid, called 7DW8-5, against a highly invasive human breast cancer cell line both in vitro and in vivo. Materials and Methods: Parental MDA-MB-231 cells and MDA-MB-231 cells transduced with human CD1d were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE), followed by loading with glycolipids. After co-culturing with human iNKT cells, the cells were permeabilized and stained with Alexa Flour 647-conjugated antibody to active caspase-3, and analyzed using a BD LSR II. For the in vivo tumoricidal effect, MDA-MB-231 cells transduced with human CD1d and luciferase genes were injected into the mammary fat pad of female NOD/SCID/IL2rγnull (NSG) mice, followed by the injection of human iNKT cells with or without 7DW8-5, and the levels of luminescence were analyzed with whole-body imaging. Results: Human iNKT cells could kill CD1d-expressing human breast cancer cells in vitro in the presence of 7DW8-5, but not α-GalCer. As for in vivo, the adoptive transfer of human iNKT cells into tumor-challenged NSG mice significantly inhibited the growth of CD1d+ MDA-MB-231 human breast cancer cells in the presence of 7DW8-5. Conclusion: CD1d-binding, glycolipid- based iNKT-cell therapy is suggested as a potent and effective treatment against breast cancer in humans.Breast cancer is a devastating disease, with different types of breast cancer recurring locally (1, 2) or distant as metastatic/advanced disease (3) following initial treatment. Metastatic breast cancer usually occurs from months to years after first treatment, and is typically found in the lungs, liver, bones or brain. Nonetheless, breast cancer recurrence is different in each patient; those differences are based on tumor biology (e.g. hormone receptor status), stage of disease when first diagnosed, or even on the chemotherapy received by the patient following diagnosis. A recent and promising treatment approach against various forms of cancer is immunotherapy, which takes advantage of the patient’s own immune system to attack the tumor cells.　
　Natural killer T-cells (NKT) are a unique subset of T-cells that share properties of both T-cells and natural killer cells. NKT cells recognize lipid antigens presented by the non-polymorphic major histocompatibility complex (MHC) class I-like molecule, CD1d (4-6). There are two major subpopulations of NKT cells: Type I NKT cells, also called invariant NKT (iNKT) cells, and type II NKT cells (7-10). The prototypic antigen for type I NKT cells is α-galactosylceramide (α-GalCer), which stimulates iNKT cells to release large amounts of interferon-γ (IFNγ), which helps activate both CD8+ T-cells and antigen-presenting cells such as dendritic cells (DCs) and macrophages (11, 12). Functionally, type I NKT cells exert a protective immune response against tumors (13-17), whereas type II NKT cells are typically associated with immunosuppression (18, 19). More recently, we identified a synthetic analog of α-GalCer, named 7DW8-5, which elicits the most potent iNKT-cell response among 100 analogs tested (20). As shown in Figure 1A, this analog differs from α-GalCer in that it possesses a fluorinated benzene ring at the end of a C8 length fatty acyl chain (20). Thus, 7DW8-5 has been shown to have stronger bioactivity towards iNKT cells and CD1d-bearing DCs (20-26). In addition, 7DW8-5 also has tumoricidal activity against human medulloblastoma in vivo, using humanized mice (17).
　In the current study, using a highly invasive and poorly differentiated triple-negative breast cancer cell line, MDA- MB-231, we investigated the ability of α-GalCer and its analog, 7DW8-5, to display NKT cell-dependent cytotoxicity against these human breast cancer cells in vitro; we then analyzed the in vivo antitumor-activating activity of 7DW8-5 using immunodeficient mice.

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