As NKG2A could inhibit the anti-MM response of these reconstituting NK cells (38), it may be an interesting option to interfere with HLA-E NKG2A interaction using a monoclonal antibody like monalizumab in the context of allo-SCT

As NKG2A could inhibit the anti-MM response of these reconstituting NK cells (38), it may be an interesting option to interfere with HLA-E NKG2A interaction using a monoclonal antibody like monalizumab in the context of allo-SCT. For a long time, feasibility of haplo-SCT was limited by the high occurrence of post-transplant complications such as GVHD and infections. pomalidomide and highly promising antibodies like daratumumab (anti-CD38) and elotuzumab (anti-CS-1/SLAMF7). Given their excellent safety and feasibility profiles, NK cells are interesting candidates to combine with these novel agents to enhance clinical efficacy and to ultimate achieve curative treatment for MM patients. Killer Immunoglobulin-Like Receptors (KIRs) Biology The KIR family consists of activating- and inhibitory receptors. Activating family members are characterized by a short cytoplasmic ITAM activating signaling domain name and are called KIRxDS. Inhibitory family members have a long and inhibitory ITIM domain name and are named KIRxDL. Both the activating and the inhibitory KIRs have two (KIR2DSx or KIR2DLx) or three (KIR3DSx or KIR3DLx) extracellular immunoglobulin-like domains for ligand conversation. Classical human leukocyte antigen (HLA) class I molecules are the most important ligands for both the activating- and the inhibitory KIRs. The best characterized inhibitory KIRs are: KIR2DL1, binding to HLA-C group 2 (C2) alleles using a lysine at position 80; KIR2DL2/3, interacting with HLA-C group 1 (C1) alleles having an asparagine at position 80 (4C6). KIR3DL1, binding HLA-B alleles bearing a Bw4 motif as well as HLA-A*23/*24/*32 (7, 8). KIR3DL2 has PAC-1 been shown to interact with HLA-A*3/*11 (9) and HLA-F (10). The activating KIR2DS1 and KIR2DS2 have been shown to bind with HIF3A C2 and C1 alleles, respectively, and KIR2DS4 interacts with subsets of HLA-C alleles and with HLA-A*11 (11, 12). The ligands for the other KIRs remain elusive so far. The genes encoding the KIRs are located in the KIR gene cluster in the leukocyte receptor region on chromosome 19, and so far, 27 different KIR haplotypes PAC-1 have been described ( KIR2DL4, KIR3DL2, KIR3DL3, and KIR3DP1 are so called framework genes and are present in all the haplotypes. Based on the additional presence/absence of the other KIRs, the haplotypes can be further grouped into haplotype-A and CB. While A haplotypes express only KIR2DS4 as activating KIR and eight other KIRs (KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, KIR2DP1, and KIR3DP1), the B haplotypes express multiple activating receptors in combination with various other genes (13). In the population, the A to B haplotype ratio is on average 1.8:1 (14) and in most populations B/x haplotypes are more common than A/A. A study comparing KIR haplotype A and B frequencies in MM exhibited that there was no difference in distribution PAC-1 between MM patients and healthy individuals (14). Moreover, analysis of KIR repertoires of 182 MM patients revealed that this genotypic presence of KIR3DS1, most pronounced in Bw4 missing patients, was associated with reduced progression free survival after autologous SCT (15). Nonetheless, further extensive studies around the influence of the KIR genetic repertoire on development and progression of MM are missing. Further variation in KIR repertoires between individuals results from the relatively polymorphic nature of the genes and expression differences can occur due to null/low/high expression allele variants and copy number variation (16). Furthermore, KIRs are acquired in a stochastic manner leading to intra-individual diversity in KIR receptor expression between NK cells (17). Within the A haplotype four inhibitory KIRs, namely KIR2DL1, KIR2DL3, KIR3DL1, KIR3DL2 can be expressed. A combination of cell surface expression of all four inhibitory KIRs is usually rarely found within one healthy individual ( 5%). Co-expression of three inhibitory KIRs occurs also in rather few NK cells (about 10%), while co-expression of 2 KIRs and expression of a single KIR occurs more frequently (30% and 35%, respectively). Functionally immature NK cells, lacking all KIRs, represent about 20% (18). NKG2A Receptor Biology NK cells of healthy individuals frequently express NKG2A (20C80%) (19, 20). NKG2A expression occurs more frequently on KIR-negative NK cells and decreases as NK cells acquire KIRs (18). NKG2A is an inhibitory member of the C-type lectin-like NKG2 receptor family that also comprises the inhibitory NKG2B and the activating NKG2C/E/H receptors.