論文 - 詳細
| RRC ID | 65607 |
|---|---|
| 著者 | Mizuta S, Tagod MSO, Iwasaki M, Nakamura Y, Senju H, Mukae H, Morita CT, Tanaka Y. |
| タイトル | Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates. |
| ジャーナル | ChemMedChem |
| Abstract |
Immune checkpoint blockade using anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non-hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy. |
| 巻・号 | 14(4) |
| ページ | 462-468 |
| 公開日 | 2019-2-19 |
| DOI | 10.1002/cmdc.201800764 |
| PMID | 30637982 |
| PMC | PMC6818088 |
| MeSH | Animals Cell Line, Tumor Diphosphonates / chemistry* Diphosphonates / pharmacology Diphosphonates / therapeutic use Fluorine / chemistry* Humans Immunologic Factors / chemical synthesis* Immunologic Factors / pharmacology Immunotherapy Intraepithelial Lymphocytes / cytology Intraepithelial Lymphocytes / drug effects Intraepithelial Lymphocytes / metabolism Lung Neoplasms / drug therapy Lung Neoplasms / metabolism Lung Neoplasms / pathology Lymphocyte Activation / drug effects Mice Prodrugs / chemical synthesis Prodrugs / pharmacology Prodrugs / therapeutic use |
| IF | 3.124 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |