NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines

Cell. 2018 Dec 13;175(7):1744-1755.e15. doi: 10.1016/j.cell.2018.10.028. Epub 2018 Nov 29.

Abstract

Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1b, the conserved ortholog of HLA-E, in four mouse tumor models. The impact of therapeutic vaccines was greatly potentiated by disruption of the NKG2A/Qa-1b axis even in a PD-1 refractory mouse model. NKG2A blockade therapy operated through CD8 T cells, but not NK cells. These findings indicate that NKG2A-blocking antibodies might improve clinical responses to therapeutic cancer vaccines.

Keywords: CD8 T cells; HLA-E; IFN-γ; NKG2A; Qa-1; acquired resistance; cancer vaccines; immune checkpoints; mouse tumor models; natural killer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neoplasm / immunology
  • Antigens, CD / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cancer Vaccines* / immunology
  • Cancer Vaccines* / pharmacology
  • Cell Line, Tumor
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immunity, Cellular*
  • Integrin alpha Chains / immunology
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily C* / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily C* / immunology
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / immunology
  • Neoplasms, Experimental* / immunology
  • Neoplasms, Experimental* / pathology
  • Neoplasms, Experimental* / therapy
  • Vaccination*

Substances

  • Antibodies, Neoplasm
  • Antigens, CD
  • Cancer Vaccines
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • Integrin alpha Chains
  • NK Cell Lectin-Like Receptor Subfamily C
  • Neoplasm Proteins
  • alpha E integrins