NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions

Cell Rep. 2021 Oct 19;37(3):109871. doi: 10.1016/j.celrep.2021.109871.

Abstract

Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A+ and NKG2A- cells characterize two distinct "intralineages" of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A+ Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.

Keywords: NKG2A immune checkpoint; Vδ2 T cells; cancer; cancer immune-therapy; hyper-reactivity; immune education.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Case-Control Studies
  • Cell Proliferation
  • Cell Self Renewal
  • Coculture Techniques
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunity, Innate
  • Infant
  • Intraepithelial Lymphocytes / immunology
  • Intraepithelial Lymphocytes / metabolism*
  • K562 Cells
  • Lymphocyte Activation*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Male
  • Middle Aged
  • NK Cell Lectin-Like Receptor Subfamily C / genetics
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phenotype
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Signal Transduction

Substances

  • Cytokines
  • KLRC1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, Antigen, T-Cell, gamma-delta