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
|
リソース情報 |
ヒト・動物細胞 |
PC-9(RCB4455) |