Oral Presentation Eradicate Cancer 2020

Butyrophilin 2A1 mediates phosphoantigen recognition and tumor targeting by gamma-delta T cells (70261)

Marc Rigau 1 2 3 , Simone Ostrouska 4 5 , Thomas S Fulford 1 , Hamish E.G. McWilliam 1 , Jose A Villadangos 1 , Jason Simmonds 6 , Matthias Pelzing 6 , Eugene Maraskovsky 6 , Con Panousis 6 , Jonathan Cebon 4 5 7 8 , Dale I Godfrey 1 3 , Andreas Behren 3 5 6 8 , Adam Uldrich 1 3
  1. Department of Microbiology & Immunology, The University of Melbourne, Melbourne, VIC, Australia
  2. University of Bonn, Bonn, Germany
  3. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Melbourne, VIC, Australia
  4. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  5. School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
  6. CSL Limited, Melbourne, VIC, Australia
  7. Ludwig Institute for Cancer Research, Heidelberg, VIC, Australia
  8. Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs), which respond to phosphoantigens (pAg) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that directly binds to the Vγ9+ TCR γ-chain. We found that BTN2A1 is highly expressed on a variety of cancer tissues and cell lines and associates with BTN3A1, which act together to initiate responses to pAg. This unique mode of MHC-independent T cell activation was essential for γδ T cell cytokine expression as well as γδ T cell-mediated killing of tumor cells. Knockout studies in melanoma cells confirmed the absolute requirement for BTN2A1 and BTN3A1 in this process. While most current immunotherapy approaches rely on (re)-activation of conventional alpha-beta (αβ) T-cells, this finding creates additional opportunities for the development of γδ T cell-based immunotherapies utilizing a different part of the immune system.