Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies.

Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity.

NK cell MHC class I specific receptors (KIR): from biology to clinical intervention.

The natural killer (NK) cell effector response towards infected cells or tumoural cells is guided by the integration of activating and inhibitory signals sensed by NK cell surface receptors. Major histocompatibility complex class I specific inhibitory receptors expressed by NK cells have two distinct roles: while allowing self tolerance, they are also needed for the acquisition of NK cell functional competence, a process termed education. In the context of allotransplantation, NK cell alloreactivity, arising from the expression on donor NK cells of inhibitory killer Ig-like receptors (KIRs) that do not recognize human leukocyte antigen from the patient, has shown clinical benefit for leukaemia patients.