Natural cytotoxicity triggering receptor 2 (NKp44) (NCR2)

Natural cytotoxicity triggering receptor 2 (NCR2), commonly known as NKp44, is a type I transmembrane glycoprotein and a member of the natural cytotoxicity receptor family (UniProt: O95944). It is primarily expressed on activated Natural Killer (NK) cells and is significantly upregulated on Cytokine-Induced Memory-Like (CIML) NK cells, which are generated through ex vivo stimulation with IL-12, IL-15, and IL-18 (Romee et al., Sci Transl Med, 2016). On these memory-like cells, NCR2 serves as a potent activating receptor that recognizes various tumor-associated ligands, such as BAG6 (BAT3), MLL5, and PDGF-DD, which are frequently upregulated in malignancies like acute myeloid leukemia (AML) and several solid tumors (Barrow et al., Front Immunol, 2019). Engagement of NCR2 triggers intracellular signaling through the DAP12 adapter protein, leading to robust NK cell degranulation, production of interferon-gamma, and direct lysis of target tumor cells. This interaction is a critical component of the 'memory-like' phenotype that allows CIML-NK cells to exhibit superior responses against myeloid leukemias compared to conventional NK cells. Therapeutic strategies currently focus on the adoptive transfer of CIML-NK cells, where the NCR2-ligand axis serves as a primary mechanism for tumor recognition and clearance (Fehniger & Cooper, Trends Immunol, 2016). Clinical trials have demonstrated the efficacy of this approach in patients with relapsed or refractory AML, highlighting the receptor's role in distinguishing malignant cells from healthy tissue. The development of CIML-NK cell products, such as WU-NK-101, continues to explore the potential of this receptor-ligand engagement in broader oncology settings.

Other names

NKp44CD336LY95Natural killer cell p44-related protein

Binding of NCR2 to tumor-associated ligands (e.g., BAG6, PDGF-DD) triggers ITAM-mediated signaling via the DAP12 adapter protein, inducing NK cell degranulation and cytokine production (Romee et al., Sci Transl Med, 2016; UniProt: O95944).