title: Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice.
abstract: Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a post-surgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (α-GalCer, α-C-GalCer or OCH) or α-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of α-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with α-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in ∼45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice.In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNγ production from natural killer (NK) cells and CD8+T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.
authors.affiliation: Department of Microbiology & Immunology; Dalhousie University ; Halifax, Nova Scotia, Canada ; Beatrice Hunter Cancer Research Institute ; Halifax, Nova Scotia, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Gebremeskel
authors.affiliation: Department of Microbiology & Immunology; Dalhousie University ; Halifax, Nova Scotia, Canada ; Beatrice Hunter Cancer Research Institute ; Halifax, Nova Scotia, Canada.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Clattenburg
authors.affiliation: Department of Microbiology & Immunology; Dalhousie University ; Halifax, Nova Scotia, Canada.
authors.forename: Drew
authors.initials: D
authors.lastname: Slauenwhite
authors.affiliation: Department of Microbiology & Immunology; Dalhousie University ; Halifax, Nova Scotia, Canada ; Beatrice Hunter Cancer Research Institute ; Halifax, Nova Scotia, Canada.
authors.forename: Lynnea
authors.initials: L
authors.lastname: Lobert
authors.affiliation: Department of Microbiology & Immunology; Dalhousie University ; Halifax, Nova Scotia, Canada ; Department of Pediatrics; Dalhousie University ; Halifax, Nova Scotia, Canada ; Department of Pathology; Dalhousie University ; Halifax, Nova Scotia, Canada ; Beatrice Hunter Cancer Research Institute ; Halifax, Nova Scotia, Canada.
authors.forename: Brent
authors.initials: B
authors.lastname: Johnston
keywords: dendritic cells; metastatic breast cancer; myeloid derived suppressor cells; natural killer T cells; tumor immunotherapy; α-GalCer, α-galacotosylceramide; ALT, alanine aminotransferase; DC, dendritic cell; FBS, fetal bovine serum; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon-γ; IL, interleukin; i.p., intraperitoneal; i.v., intravenous; MDSC, myeloid derived suppressor cell; NK cell, natural killer cell; NKT cell, natural killer T cell; RPMI-1640, Roswell Park Memorial Institute medium-1640; TCR, T cell receptor; Th, T helper.