BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells

Cell Rep. 2021 Jul 13;36(2):109359. doi: 10.1016/j.celrep.2021.109359.

Abstract

The anti-tumor response of Vγ9Vδ2 T cells requires the sensing of accumulated phosphoantigens (pAgs) bound intracellularly to butyrophilin 3A1 (BTN3A1). In this study, we show that butyrophilin 2A1 (BTN2A1) is required for BTN3A-mediated Vγ9Vδ2 T cell cytotoxicity against cancer cells, and that expression of the BTN2A1/BTN3A1 complex is sufficient to trigger Vγ9Vδ2 TCR activation. Also, BTN2A1 interacts with all isoforms of BTN3A (BTN3A1, BTN3A2, BTN3A3), which appears to be a rate-limiting factor to BTN2A1 export to the plasma membrane. BTN2A1/BTN3A1 interaction is enhanced by pAgs and, strikingly, B30.2 domains of both proteins are required for pAg responsiveness. BTN2A1 expression in cancer cells correlates with bisphosphonate-induced Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell killing of cancer cells is modulated by anti-BTN2A1 monoclonal antibodies (mAbs), whose action relies on the inhibition of BTN2A1 binding to the Vγ9Vδ2TCR. This demonstrates the potential of BTN2A1 as a therapeutic target and adds to the emerging butyrophilin-family cooperation pathway in γδ T cell activation.

Keywords: BTN2A1; BTN3A; Vγ9Vδ2 T cells; butyrophilins; cancer; immunotherapy; monoclonal antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antigens / metabolism
  • Antigens, CD / metabolism
  • Butyrophilins / metabolism*
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • HEK293 Cells
  • Humans
  • Immune Checkpoint Proteins / metabolism*
  • Lymphocyte Activation / immunology
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Antibodies, Monoclonal
  • Antigens
  • Antigens, CD
  • BTN2A1 protein, human
  • BTN3A1 protein, human
  • Butyrophilins
  • Immune Checkpoint Proteins
  • Receptors, Antigen, T-Cell, gamma-delta