Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates.

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 ?? T?cells and ?? T?cells. In contrast to conventional ?? T?cells that recognize peptides in the context of MHC class?I or II molecules, ?? T?cells expressing V?2V?2 T?cell receptors (also termed V?9V?2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. V?2V?2 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 V?2V?2 T?cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced V?2V?2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood V?2V?2 T?cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand V?2V?2 T?cells for adoptive cell therapy.

SUBMITTER: Mizuta S 

PROVIDER: S-EPMC6818088 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature