Disruption of the NKG2A:HLA-E Immune Checkpoint Axis to Enhance NK Cell Activation against Cancer

Abstract

Ligation of the inhibitory receptor NKG2A by its ligand HLA-E negatively regulates the activation of natural killer (NK) cells, as well as subsets of CD8+ T cells and innate T cell populations. NKG2A has recently become a novel immune checkpoint target for the treatment of cancer and direct antibody mediated blockade of NKG2A function is currently under assessment in two phase 3 clinical trials. In addition to direct targeting, the NKG2A:HLA-E axis can also be disrupted indirectly via multiple different targeted cancer agents that were not previously recognised to possess immunomodulatory properties. Increased understanding of immune cell modulation by targeted cancer therapies will allow for the design of rational and more efficacious drug combination strategies to improve cancer patient outcomes. In this review, we summarise and discuss the various strategies currently in development which either directly or indirectly disrupt the NKG2A:HLA-E interaction to enhance NK cell activation against cancer.

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics

“…NK cell exhaustion has been observed in an immunosuppressive TME and characterized by reduced activating receptors, decreased production of effector cytokines ( 181 ), impaired signaling/transcriptional pathways, hypoxia ( 182 ), low pH ( 183 ), upregulation of inhibitory receptors like NKG2A, TIM-3, PD-1, TIGIT, LAG-3, KIR ( 184 , 185 ), and the presence of Tregs ( 186 ), Bregs ( 187 ), and MDSCs ( 188 ). This NK cell exhaustion phenotype presents a significant obstacle to developing NK cell-targeting immunotherapies.…”

Harnessing natural killer cell effector function against cancer

“…In accordance with this, NKG2A+ NK cells are detected in tumour draining lymph nodes, the first site for metastases in patients with breast cancer [ 115 ]. Additionally, disruption of NKG2A function may have particular importance in combination with adoptive NK-cell therapies because clinically relevant NK-cell expansion techniques lead to significantly increased surface NKG2A expression (reviewed in [ 116 ]).…”

“…In addition to monalizumab, the NKG2A blocking antibody BMS-986315 is currently in a phase 1/2 trial for patients with advanced solid tumours either alone or in combination with nivolumab or cetuximab (NCT04349267). In addition to direct antibody-mediated blockade of NKG2A, other approaches under investigation include antibody-mediated blockade of HLA-E, as well as CRISPR-Cas9 mediated silencing of NKG2A expression [ 116 , 119 , 120 ]. Interestingly, tumour cell surface expression of HLA-E is sensitive to downregulation by various clinically relevant pharmacological agents such as the XPO1 inhibitor selinexor, the proteosome inhibitor bortezomib, and the cyclin-dependent kinase inhibitor dinaciclib [ 112 , 121–123 ].…”

CD8 + T cell targeting of tumor antigens presented by HLA-E

“…A well-known example of this strategy is human cytomegalovirus (HCMV) which eliminates endogenous VL9 by degrading nascent MHC-Ia and blocking TAP while encoding a viral VL9 peptide in the gene UL40 which is loaded onto HLA-E independent of TAP, thus ensuring high levels of HLA-E expression despite inhibition of MHC-Ia antigen presentation ( 14 , 15 ). Up-regulation of HLA-E has also been reported for gynecological, breast, non–small cell lung, renal cell, and colorectal cancers, and this up-regulation often correlates with NKG2A expression on a large percentage of tumor-infiltrating CD8 + T cells (TILs) [reviewed in ( 11 , 16 )]. A particularly notable example was reported for human papilloma virus (HPV)–positive head and neck cancers where 50% of the CD8 + tumor–infiltrating lymphocytes expressed NKG2A/CD94, whereas CD8 + T cells in the blood rarely expressed this inhibitory receptor ( 17 ).…”

“…The HLA-E/NKG2A ligand receptor pair thus seems to represent an immune checkpoint that limits both the effectiveness of tumor-infiltrating NK cells and tumor antigen–targeting T cells ( 11 , 18 ). For this reason, NKG2A-targeting antibodies are now in clinical testing and have shown some promise, particularly in combination with immunotherapies ( 16 , 19 , 20 ). In addition, these antibodies might improve the activity of active vaccination against tumor antigens ( 17 , 21 ).…”