KIR Immune Checkpoint Molecule for Drug Development

Immune Checkpoint Molecule KIR

Killer immunoglobulin-like receptor (KIR, CD158) is a regulatory glycoprotein belonging to the superfamily of immunoglobulin that recognizes MHC class I molecules and modulates cell-mediated cytotoxicity. It negatively regulates the natural killer (NK) function to protect cells from NK-mediated cell lysis. Also, its ability to prevent the formation of an activation platform and inhibit NK cell activation is the basis of the missing self-model of NK cell function. 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. To learn more about the KIR-involved pathway, please visit KIR and MHC I pathway.

Table.1 Immune checkpoint KIR.

Checkpoint receptor	Alternate name	Cell type affected	Ligand
KIR	CD158	Naive T and B cells, further upregulated on the activation	MHC

Structure of KIR

KIR molecules contain 2-3 Ig ectodomains and cytoplasmic tails of variable length. Depending on the number of extracellular immunoglobulin-like domains, KIRs are divided into two distinct groups. Some 'noninhibitory' KIRs have truncated cytoplasmic tails, containing one domain that stimulates the cytotoxic activity of NK cells. Other KIRs possess longer tails containing two inhibitor-type domains (immunoreceptor tyrosine-based inhibitory motifs; ITIMs) that mediate downstream signaling and confer anti-NK potential.

Expression of KIR

KIR is generally expressed on NK cells and may also be expressed on some T cells, such as CD8⁺ T cells. It modulates the cytotoxic activity of both cell types and assists with the self-recognition of host cells through MHC-I binding. Inhibitory KIRs are selectively expressed in the peritumoral NK cell and thus seem to be a checkpoint pathway coopted by tumors, similar to PD-L1.

Function of KIR

NK cells lack meticulous antigen sensitivity and instead rely on several activating and inhibitory receptors to modulate and direct their killing capacity. Being a family of inhibitory or activating receptors, the primary function of KIR is to protect normal cells from autologous NK-mediated cytotoxic activity. KIR induces NK tolerance through a process of 'licensing', in which each inhibitory receptor could recognize a self HLA class I molecule and prevent NK activation against autoantigens and self-tissue. KIR is also involved in TCR signaling. Recently, some studies have demonstrated that a lack of KIR ligands or KIR ligand incompatibility with foreign tissues is associated with improved survival and lower relapse rates. Therefore, KIR inhibition is a viable means of enabling or augmenting NK cell-mediated anti-tumor lytic activity.

Clinical Development of Drugs Targeting KIR

KIR is thought of as an immune checkpoint molecule; blocking KIR on NK cells could be exploited to interfere with MHC-I interactions and stimulate NK cells by mimicking the 'missing self' response and augment anti-tumor immunity. The main advantage of targeting KIR is activating mostly NK cells rather than T cells, a potentially synergistic antitumor approach for allowing other forms of immunotherapy at the same time. To that end, different molecules targeting KIR are under investigation and have entered clinical testing.

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