2. Academic Validation
  3. The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent

The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent

  • Cell Rep. 2023 Dec 3;42(12):113516. doi: 10.1016/j.celrep.2023.113516.
Jim Middelburg 1,  Soroush Ghaffari 2,  Tom A W Schoufour 3,  Marjolein Sluijter 1,  Gaby Schaap 1,  Büsra Göynük 1,  Benedetta M Sala 4,  Lejla Al-Tamimi 4,  Ferenc Scheeren 5,  Kees L M C Franken 6,  Jimmy J L L Akkermans 3,  Birol Cabukusta 3,  Simone A Joosten 6,  Ian Derksen 3,  Jacques Neefjes 3,  Sjoerd H van der Burg 1,  Adnane Achour 4,  Ruud H M Wijdeven 3,  Jon Weidanz 7,  Thorbald van Hall 8
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
  • 2 Department of Biology, College of Science, The University of Texas at Arlington, Arlington, TX, USA.
  • 3 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
  • 4 Science for Life Laboratory, Department of Medicine, Karolinska Institute & Division of Infectious Diseases, Karolinska University Hospital, 171 65 Solna, Sweden.
  • 5 Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
  • 6 Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands.
  • 7 Abexxa Biologics, Inc., Arlington, TX, USA; College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, USA.
  • 8 Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: t.van_hall@lumc.nl.
PMID: 38048225 DOI: 10.1016/j.celrep.2023.113516
Abstract

The immune checkpoint NKG2A/CD94 is a promising target for Cancer Immunotherapy, and its ligand major histocompatibility complex E (MHC-E) is frequently upregulated in Cancer. NKG2A/CD94-mediated inhibition of lymphocytes depends on the presence of specific leader Peptides in MHC-E, but when and where they are presented in situ is unknown. We apply a nanobody specific for the Qdm/Qa-1b complex, the NKG2A/CD94 ligand in mouse, and find that presentation of Qdm peptide depends on every member of the endoplasmic reticulum-resident peptide loading complex. With a turnover rate of 30 min, the Qdm peptide reflects antigen processing capacity in real time. Remarkably, Qdm/Qa-1b complexes require inflammatory signals for surface expression in situ, despite the broad presence of Qa-1b molecules in homeostasis. Furthermore, we identify LILRB1 as a functional inhibition receptor for MHC-E in steady state. These data provide a molecular understanding of NKG2A blockade in immunotherapy and assign MHC-E as a convergent ligand for multiple immune checkpoints.

Keywords

CP: Cancer; CP: Immunology; LILRB1; MHC-E; NKG2A; immune checkpoint; immunotherapy of cancer; inflammation; interferon; peptide-loading complex.

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