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A Cell‐Permeable Phosphoantigen Prodrug Increases Response of Vγ9Vδ2 T Cells to Target Cells
Author(s) -
Kilcollins Ashley,
Li Jin,
Hsiao ChiaHung,
Wiemer Andrew
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.888.4
Subject(s) - lysis , prodrug , k562 cells , chemistry , flow cytometry , cell , t cell , microbiology and biotechnology , cancer research , biochemistry , immune system , biology , immunology
Vγ9Vδ2 T cells recognize and lyse cells containing small phosphorous compounds known as phosphoantigens. Here, we utilize a synthetic cell‐permeable phosphoantigen prodrug, bis(pivaloyloxymethyl) ( E )‐4‐hydroxy‐3‐methyl‐but‐2‐enyl phosphonate (POM 2 ‐C‐HMBP), to assess the mechanisms of uptake and target cell lysis. We analyzed the effects of POM 2 ‐C‐HMBP and the known phosphoantigen ( E )‐4‐hydroxy‐3‐methyl‐but‐2‐enyl diphosphate (HMBPP) on 1) proliferation of Vγ9Vδ2 T cells using spectrophotometry and 2) Vγ9Vδ2 T cell‐mediated lysis of K562 cells using flow cytometry and live imaging. Treatment with POM 2 ‐C‐HMBP increased proliferation of Vγ9Vδ2 T cells compared to treatment with HMBPP. Pretreatment of K562 cells with POM 2 ‐C‐HMBP sensitized them to T cell‐mediated lysis more efficiently than pretreatment with HMBPP. Pretreatment at 4°C decreased lysis of K562 cells pretreated with HMBPP but did not alter lysis of cells pretreated with POM 2 ‐C‐HMBP. Our results show that the enhanced activity of prodrugs are likely due to their ability to bypass normal endocytic pathways required for entry of natural phosphoantigens, which are negatively charged. The ability to target and increase the response of Vγ9Vδ2 T cells to malignant cells may be a promising strategy for cancer immunotherapy. Financial support from the University of Connecticut Department of Pharmaceutical Sciences is gratefully acknowledged.