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The NKG2A–HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment

Linda Borst, Sjoerd H. van der Burg and Thorbald van Hall
Linda Borst
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
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  • For correspondence: t.van_Hall@lumc.nl L.Borst@lumc.nl
Sjoerd H. van der Burg
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
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  • ORCID record for Sjoerd H. van der Burg
Thorbald van Hall
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
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DOI: 10.1158/1078-0432.CCR-19-2095 Published November 2020
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Abstract

The success of checkpoint blockade therapy revolutionized cancer treatment. However, we need to increase the fraction of responding patients and overcome acquired resistance to these therapies. Recently, the inhibitory receptor NKG2A received attention as a new kid on the block of immune checkpoints. This receptor is selectively expressed on cytotoxic lymphocytes, including natural killer cells and CD8 T cells, and NKG2A+ T cells are preferentially residing in tissues, like the tumor microenvironment. Its ligand, histocompatibility leucocyte antigen E (HLA-E), is a conserved nonclassical HLA class I molecule that binds a limited peptide repertoire and its expression is commonly detected in human cancer. NKG2A blockade as a standalone therapy appears poorly effective in mouse tumor models, however, in the presence of activated T cells, for example, induced by PD-1/PD-L1 blockade or cancer vaccines, exerts strongly enhanced efficacy. Clinical trials demonstrated safety of the humanized NKG2A-blocking antibody, monalizumab, and first results of phase II trials demonstrate encouraging durable response rates. Further development of this axis is clearly warranted.

Footnotes

  • Clin Cancer Res 2020;26:5549–56

  • Received January 27, 2020.
  • Revision received March 31, 2020.
  • Accepted May 12, 2020.
  • Published first May 14, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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The NKG2A–HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment
Linda Borst, Sjoerd H. van der Burg and Thorbald van Hall
Clin Cancer Res November 1 2020 (26) (21) 5549-5556; DOI: 10.1158/1078-0432.CCR-19-2095

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The NKG2A–HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment
Linda Borst, Sjoerd H. van der Burg and Thorbald van Hall
Clin Cancer Res November 1 2020 (26) (21) 5549-5556; DOI: 10.1158/1078-0432.CCR-19-2095
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  • Article
    • Abstract
    • Introduction
    • The Similarities and Differences within the NKG2A Family
    • Expression and Function of NKG2A in Cytotoxic Lymphocytes
    • HLA-E as a Molecule of Immune Tolerance
    • HLA-E Expression in Cancer
    • Induction of HLA-E
    • Targeting the NKG2A–HLA-E Axis
    • NKG2A in Clinical Trials
    • Conclusions
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
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Clinical Cancer Research
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