The NKG2A / HLA-E axis as a novel target for immune checkpoint therapy

Author(s):
Borst, L.
Published
2022
Publication type
Doctoral Thesis

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, HLA-E, is a conserved non-classical 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, displays 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.

Cancer immunotherapyNKG2AHLA-ECheckpoint blockadeCancer vaccinationsCombination therapyAcquired resistance
Defense date
2022-06-30
Language
English
Supervisor(s)
Hall, T. van; Burg, S.H. van der
Committee member(s)
Ossendorp, F.A.; Joosten, S.A.; Adema, G.J.; Aerts, J.G.J.V.
Qualification
Ph.D.
Degree granting institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University, Leiden
hdl
1887/3421541
ISBN(s)
9789464238655

Funding

Sponsorship
The research described in this thesis was performed at the department of medical oncology at the Leiden University Medical Center, The Netherlands. The work described in this thesis was funded by the grant of the Dutch Cancer Society (2014-7146)