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Publications

Journal Article Epublish

PubMed: 42828364 DOI: 10.1021/acsptsci.6c00264

Insights into the Mechanism of Action of Phosphoantigen Prodrugs on Vγ9Vδ2 T Cell Activation.

ACS Pharmacol Transl Sci 9(9):2585-2594

Authors: Maria Sharif, Claudia M A Pinna, Kamila Rakhimova, Taher E Taher, Andrew D Beggs, Youcef Mehellou, Benjamin E Willcox

Affiliations

  • Cancer Immunology and Immunotherapy Centre, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
  • School of Infection, Inflammation and Immunology, Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
  • School of Medical Sciences, Department of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
  • School of Medical Sciences, Department of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, U.K.
  • Cancer Immunology and Immunotherapy Centre, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. School of Infection, Inflammation and Immunology, Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
  • University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, U.K.
  • School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, U.K.
  • Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, U.K.
  • Cancer Immunology and Immunotherapy Centre, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. School of Infection, Inflammation and Immunology, Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K. National Institute for Health and Care Research (NIHR), Birmingham Biomedical Research Centre, Birmingham B15 2TH, U.K.

Abstract

The activation of Vγ9Vδ2 T cells has emerged as a promising modality in cancer immunotherapy. Phosphate and phosphonate prodrugs of Vγ9Vδ2 T cell phosphoantigens have been developed as potent activators of Vγ9Vδ2 T cells that are capable of effectively facilitating lysis of a range of cancer cells in vitro. In this work, we show that phosphonate prodrugs of the phosphoantigen derivative, HMBP, enter cells in an energy-independent manner and produce their pharmacological activity independently of the mevalonate pathway, a target of the widely used bisphosphonate and Vγ9Vδ2 T cell activator, zoledronate. Interestingly, these prodrugs, termed HMBP ProPAgens, induced an enhanced and more universal Vγ9Vδ2 T cell cytotoxicity against diverse cancer cell lines in vitro compared to zoledronate, an effect also observed in patient-derived colorectal cancer organoids. Together, the data presented in this work further support the development of HMBP ProPAgens as a novel class of cancer immunotherapeutic agents.

MeSH

Cells, Neoplasms, Work, Prodrugs, T-Lymphocytes