KIR and MHC I Pathway

Introduction

Killer cell Ig-like receptors (KIR; CD158) constitute a family of MHC-I binding receptors that play a significant role in regulating the activation thresholds of NK cells and some T cells in humans. KIRs comprise a diverse repertoire of MHCI binding molecules that recognize distinct subsets of the classical human MHC-I molecules, HLA-A, -B, and -C.

Like the T cell receptor (TCR), KIR binds to HLA across the peptide-binding groove of MHC-I; however, unlike the TCR, KIR only contacts the C-terminal end of the peptide presented on MHC-I. KIRs negatively regulate NK function to protect NK-mediated cell lysis and promote self-tolerance by dampening lymphocyte activation, cytotoxic activity, and cytokine release. KIR aids in the identification and destruction of cells that have lost their MHC-I as with many tumor cells, a process termed 'missing self' recognition. Some malignancies, however, develop mechanisms to evade this pathway by either upregulating non-classical MHC-I molecules or by changing the tumor microenvironment properties rendering NK cells dysfunctional.

Preclinical and Clinical Development of Drugs for KIR and MHC I Pathway

Since inhibitory KIR plays a prominent role in regulating NK cell activation, a therapeutic strategy designed to blocking the KIR signal is a viable means of enabling or augmenting NK cell-mediated antitumor lytic activity. Recent reports have demonstrated that KIR blockade using anti-KIR antibodies has been shown to prevent tolerogenic and reconstitute NK-mediated cell lysis in both in vivo and in vitro cancer models. Together, these reports provide preclinical evidence that KIR blockade may be a therapeutically viable option to boost NK cell-mediated cytotoxicity responses toward tumors in cancer patients. Based on these studies, many new drugs targeting NK cells are currently under investigation and tested in clinics. The most advanced compound targeting the NK cell population is a blocking anti-KIR monoclonal antibody. Moreover, different treatment combinations providing additional activating signals to NK cells could synergize with anti-KIR mAb, like drugs that activate NK cell ligands on tumor cells (chemotherapy) or that boost NK cell activity (cytokines or therapeutic mAbs working through ADCC).

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