SummaryCheckpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
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We have characterized the heterogeneity of human blood NK cell subsets defined by expression of KIR, lectin like receptors and NK cell differentiation markers within a cohort of 51 healthy Caucasian individuals. High inter‐individual variability in cell surface expression of most NK cell markers is observed. Range values defining NK cell subsets in healthy donors were further used as references to characterize 14 patients with NK‐type lymphoproliferative disease of granular lymphocytes (NK‐LDGL). Alterations of the KIR repertoire were noted in all NK‐LDGL patients. NK cell expansions were classified as oligoclonal KIR+ or as non‐detectable KIR (ndKIR) using anti‐KIR2DL1/2DS1, anti‐KIR2DL2/2DL3/2DS2, anti‐KIR3DL1 and anti‐KIR2DS4 monoclonal antibodies. A major reduction in the size of the CD56bright NK cell subset was a constant feature of NK‐LDGL. Altered distribution of CD94+, CD161+, and CD162R+ NK cell subsets was also observed in NK‐LDGL patients. Considering the potential role of NK cells in eliminating tumors or virus‐infected cells, the reference values defined in this study should be valuable to characterize both quantitative and qualitative alterations of the NK cell repertoire in pathological conditions and to monitor NK cell reconstitution following hematopoietic transplantation.
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