In vivo anti-tumour safety and efficacy of NK cell-based immunotherapeutic approach in preclinical models

Despite significant advances in the treatment of haematological malignancies, the high clonal heterogeneity of cancer cells often leads to relapse and the development of treatment resistance. This challenge has prompted the exploration of new therapeutic strategies, with immunotherapy emerging as a promising approach. Endoplasmic reticulum aminopeptidase 1 (ERAP1) has previously been identified as a key player in antigen processing, trimming peptides that are presented by HLA class I molecules to immune cells. Recent studies have highlighted the therapeutic potential of ERAP1 inhibition, which can modify the immunopeptidome and enhance anti-tumour immune responses. In this study, we found that ERAP1 inhibition, by altering antigens bound to HLA class I molecules in haematological malignancies, disrupts interactions with natural killer (NK) cell inhibitory receptors, resulting in increased cytotoxicity of NK cells. We demonstrate for the first time that ERAP1 is essential for the delivery of HLA-E molecules, which are often highly expressed by cancer cells as an immune evasion mechanism. Knockout of ERAP1 (KO) results in reduced expression of HLA-E molecules on the cell surface. In addition, it impairs the binding of the NKG2A inhibitory receptor of NK cells to tumour cells, resulting in enhanced cytotoxicity of NK cells. These findings highlight ERAP1 as a potential new therapeutic target for NK-cell-based immunotherapy of haematological malignancies.