The CD94/NKG2A–HLA-E Axis as a Target in Cancer Immunotherapy: A Critical Perspective

Successful clinical development of PD-1/PD-L1 and CTLA4 immune checkpoint blockers intensified the search for other potential targets for cancer immunotherapy. Among them, the CD94/NKG2A inhibitory receptor displayed by NK cell and T-cell subsets, which specifically interacts with the nonclassic HLA-E class I molecule, has attracted special attention. Here, we provide an overview of basic concepts on the CD94/NKG2A-HLA-E axis biology relevant in the framework of ongoing cancer immunotherapy approaches in different scenarios. First, the effectiveness of blocking the NKG2A-HLA-E interaction in vitro and in preclinical models as well as the presence of infiltrating NKG2A+ CD8+ T cells in some solid tumors has led to the generation of clinical-grade NKG2A-specific monoclonal antibodies, pioneered by monalizumab, currently tested in clinical trials. Second, controlling NKG2A expression by genetic engineering constitutes a promising approach to improve advanced adoptive NK cell-based immunotherapies. Challenges include identifying predictive biomarkers of responsiveness, selecting appropriate clinical settings, and optimizing combinatorial regimens.