Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity
| Autor: | Santosh Keshipeddy, Xiangshu Wen, Weiming Yuan, Jae Ho Lo, Jérôme Le Nours, Dale I. Godfrey, Matthew J. Guberman-Pfeffer, Steven A. Porcelli, Divya Chennamadhavuni, Leandro J. Carreño, Rhys Pryce, Jamie Rossjohn, Tang Yongqing, Stewart K. Richardson, Noemi Alejandra Saavedra-Avila, Amy R. Howell, José A. Gascón, Hui-Fern Koay, Pooja Arora, Srinivasan Sundararaj |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Clinical Biochemistry Cell 02 engineering and technology Lymphocyte Activation 01 natural sciences Biochemistry Mice 0302 clinical medicine Antineoplastic Agents Immunological α galactosylceramide Cancer immunotherapy Neoplasms Drug Discovery Cells Cultured Antitumor immunity biology 021001 nanoscience & nanotechnology Natural killer T cell 3. Good health Cell biology Molecular Docking Simulation medicine.anatomical_structure Cytokine CD1D Molecular Medicine Female Immunotherapy 0210 nano-technology Adult Adolescent Chemical biology Galactosylceramides 010402 general chemistry Article Proinflammatory cytokine 03 medical and health sciences Immune system Cell Line Tumor medicine Animals Humans Invariant natural killer T-cell Molecular Biology Aged Pharmacology 0104 chemical sciences Mice Inbred C57BL 030104 developmental biology biology.protein Natural Killer T-Cells Antigens CD1d 030215 immunology |
| Zdroj: | Cell chemical biology. 25(7) |
| ISSN: | 2451-9448 2451-9456 |
| Popis: | Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α‐galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly pro-inflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α‐galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings, and suggested basic principles for capturing useful properties of sphinganine analogues of synthetic iNKT cell activators in the design of immunotherapeutic agents. |
| Databáze: | OpenAIRE |
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