Natural cytotoxicity trigger receptor 2 ligand (NKp44L)

Natural cytotoxicity trigger receptor 2 ligands (NKp44L) are a diverse group of molecules expressed on the surface of transformed or stressed cells, including multiple myeloma cells, that interact with the NKp44 (NCR2) receptor on Natural Killer (NK) cells (Baychelier et al., 2013). A primary activating ligand identified in malignancies is a specific 21-kDa isoform of Mixed-lineage leukemia protein 5 (MLL5), which is expressed on the surface of tumor cells but absent from healthy tissues (Blood, 2013). Other ligands include BAG6 (BAT3), which promotes NK cell-mediated killing, and surface-expressed PCNA, which paradoxically acts as an inhibitory ligand to facilitate tumor immune escape (Horton & Mathew, 2015). In multiple myeloma, the presence of these ligands is a critical determinant of the susceptibility of malignant plasma cells to NK cell surveillance (El-Sherbiny et al., 2007). Therapeutic interest in NKp44L focuses on its role as a tumor-specific marker for redirected immunotherapy. Experimental approaches include the use of NKp44-Ig fusion proteins to enhance recognition or the development of CAR-T and CAR-NK cells engineered with NKp44-based chimeric receptors to target the ligand-expressing myeloma niche (Journal of Immunology, 2011). However, the clinical utility of targeting NKp44L is challenged by the shedding of these molecules into the systemic circulation; soluble NKp44L (sNKp44L) can act as a decoy, neutralizing the NKp44 receptor and correlating with poor prognosis in cancer patients (Pogge von Strandmann et al., 2007).

Other names

NKp44 ligandNCR2 ligandMixed-lineage leukemia protein 5 (isoform)MLL5BAG6BAT3Proliferating cell nuclear antigen (surface-expressed)

Engagement of the NKp44 activating receptor on Natural Killer cells to trigger the release of cytotoxic granules and pro-inflammatory cytokines against ligand-expressing tumor cells.