Abstract
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a postsurgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogues enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1, and ATP). In 4T1 primary tumor and postsurgical metastasis models, BALB/c mice were treated with cyclophosphamide or gemcitabine. NKT cells were then activated by transfer of dendritic cells loaded with the glycolipid antigen α-galactosylceramide (α-GalCer). Chemotherapeutic treatments did not impact NKT-cell activation but enhanced recruitment into primary tumors. Cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cell monotherapies decreased tumor growth in the primary tumor model and reduced metastatic burden and prolonged survival in the metastasis model. Combining chemotherapeutics with NKT-cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. The frequency of myeloid-derived suppressor cells was reduced by gemcitabine, cyclophosphamide, or α-GalCer-loaded dendritic cell treatments; cyclophosphamide also reduced the frequency of regulatory T cells. Individual treatments increased immune cell activation, cytokine polarization, and cytotoxic responses, although these readouts were not enhanced further by combining therapies. These findings demonstrate that NKT-cell activation therapy can be combined with gemcitabine or cyclophosphamide to target tumor burden and enhance protection against tumor recurrence. Cancer Immunol Res; 5(12); 1086-97. ©2017 AACR.
Highlights
Invariant natural killer T (NKT) cells are a specialized population of T cells with restricted T-cell receptor (TCR) rearrangements, Va14-Ja18 paired with Vb8.2/7/2 in mice and Va24-Ja18 paired with Vb11 in humans, that recognize endogenous and pathogen-derived glycolipid antigens presented via the nonpolymorphic MHC-like molecule CD1d (1)
Effect of chemotherapeutics on tumor immunogenicity We investigated whether gemcitabine or mafosfamide could alter the expression of MHC molecules on tumor cells
Using a mouse model of breast cancer metastasis, we previously demonstrated that NKT-cell activation reduces metastatic burden, stimulates antitumor immunity, and improves survival (5)
Summary
Invariant natural killer T (NKT) cells are a specialized population of T cells with restricted T-cell receptor (TCR) rearrangements, Va14-Ja18 paired with Vb8.2/7/2 in mice and Va24-Ja18 paired with Vb11 in humans, that recognize endogenous and pathogen-derived glycolipid antigens presented via the nonpolymorphic MHC-like molecule CD1d (1). NKT cells regulate innate and adaptive immune responses and contribute to tumor immu-. Nosurveillance (2), likely through detection of stress-induced glycolipids, tumor-associated glycolipid antigens, and/or inflammatory cytokines. Therapeutic NKT-cell activation provides protection from tumor development and progression in animal models (3–9), and induces lasting antitumor immunity (5, 7). NKT-cell activation therapies stabilized disease in head and neck cancer patients (10, 11) and prolonged median survival time in lung cancer patients (12). Activated NKT cells can kill tumor cells directly (13–15) or indirectly by regulating the activation and function of T cells (5, 7–9, 16–18), NK cells (4, 5, 8, 9, 17), dendritic cells NKT-cell activation inhibits tumor angiogenesis (6), eliminates tumor-infiltrating monocytes (20), and inhibits the activity of tumor-induced myeloid-derived suppressor cells NKT-cell activation inhibits tumor angiogenesis (6), eliminates tumor-infiltrating monocytes (20), and inhibits the activity of tumor-induced myeloid-derived suppressor cells (MDSCs; ref. 5)
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