Although T cells have commanded most of the attention in the burgeoning immuno-oncology field, there is a growing appreciation that other immune cells have important roles in tumor surveillance and would represent attractive therapeutic targets.
As the body’s first line of defense, natural killer (NK) cells have gradually emerged as just such a target. Analogous checkpoint receptors expressed on their surface that regulate activation and inhibition of NK cell cytotoxic activity offer a particularly promising avenue for drug development.
In order to manipulate these cells, researchers have been focusing on the killer cell immunoglobulin-like receptor (KIR) pathway, one of the central receptor families involved in NK cell activation. Innate Pharma and Bristol-Myers Squibb are leading the field with their joint development of lirilumab, a monoclonal antibody that targets KIR.
While the path to regulatory approval for this drug class is not wrinkle free, recent data suggest a potentially significant role for this treatment paradigm in rational combinations of immunotherapy and targeted therapy that capitalize on their unique mechanism of action.
Natural Born Killers
First discovered more than 40 years ago, the NK cells are called "natural killers" because of their ability to rapidly kill target cells without having to be primed first, for example, by exposure to an antigen, as is necessary for T cells.
These cells are on the front line of the body’s innate immune response, patrolling the body on high alert, ready to kill when they encounter target cells including virally infected and cancerous cells.
Although the speed with which the NK cells can kill is highly advantageous, it could prove very dangerous to normal cells if they were to kill indiscriminately; thus, their activation is tightly regulated. This is achieved through a delicate balance between activating and inhibitory receptors expressed on the surface of the NK cell.
The best-defined ligands of the inhibitory receptors are the major histocompatibility complex (MHC) class I proteins that take peptides from within the cell and present them on the surface to help identify a cell as “self” or “non-self.” Self-MHC class I proteins are found on the surface of all normal cells of the body and, when confronted by an NK cell, they bind to the inhibitory receptors on its surface and suppress NK-cell activity.
To become activated, the NK cell requires reversal of this inhibition, which is achieved when a cell that does not express self-MHC class I molecules is encountered (detection of missing self), as well as stimulation of the activating receptors. The latter occurs when the target cell expresses the ligands that bind these receptors; for example, the stress ligands that are expressed by cancer cells resulting from their extensive DNA damage. Combined stimulation of the activating receptors and lack of suppression of the inhibitory receptors shift the balance in favor of NK cell activation.
NK cells are derived from hematopoietic stem cells in the bone marrow and differentiate into large, granular mature NK cells that comprise between 5% and 20% of the total population of circulating lymphocytes. The granules they contain are composed of the membrane-disrupting protein perforin and proteolytic enzymes called granzymes. Once activated, the NK cell tightly associates with the target cell, forming what is known as an immunological synapse in recognition of its resemblance to a nervous system synapse. This allows the granules to be passed from the NK cell to the target cell, where they cause cell lysis and death.
NK cells can also kill target cells in several other ways, including by expressing the tumor necrosis factor (TNF) and death-inducing ligands, such as the TNF-related apoptosis-inducing ligand (TRAIL), both of which bind to death-inducing receptors on the surface of the target cell, triggering programmed cell death. NK cells also produce a variety of cytokines and chemokines that can attract other immune cells to the target cell location.
Studies have now shown that NK cells play an important role in the antitumor immune response, but tumors also appear to have evolved mechanisms of overcoming NK cell–mediated immune surveillance. Depletion of NK cells or impaired NK cell function has been noted in various cancer types.
KIRs Play Dual Immune System Roles
One of the central receptor families involved in NK-cell activation is the KIRs, encoded by a group of 15 functional and 2 pseudogenes found within a section of chromosome 19 known as the leukocyte receptor complex.
When it comes to their regulation of NK-cell cytotoxicity, KIRs can be either activating or inhibitory, with their structure determining their function as well as the types of ligands with which they interact.