Natural killer (NK) cells are a type of white blood cell that forms a specialized part of the body’s immune system. These cells function as immediate defenders, constantly patrolling the body to identify and eliminate foreign or abnormal cells, including those that have become cancerous. NK cells are a component of the body’s innate immune surveillance, offering a rapid, non-specific response to cellular threats.
Natural Killer Cells: The Immune System’s Specialized Force
Natural killer cells are lymphocytes belonging to the innate immune system, which provides the body’s first line of defense. Unlike T-cells of the adaptive immune system, NK cells do not require prior exposure to a specific threat to become active. They are equipped to kill upon detection, allowing for an immediate response to newly emerging threats like cancer.
Their primary role is immune surveillance, which involves scanning the body for cells that show signs of stress, infection, or malignant transformation. This function is accomplished by balancing signals received through activating and inhibitory receptors on the NK cell surface. These cells also orchestrate the broader immune response by releasing signaling proteins called cytokines, which direct other immune cells to the site of danger.
The Unique Mechanism of Cancer Cell Recognition and Destruction
The ability of NK cells to distinguish a healthy cell from a cancerous one is governed by a system of checks and balances involving surface receptors. Healthy cells display Major Histocompatibility Complex (MHC) Class I on their surface, which acts as a “self” marker. NK cells possess inhibitory receptors that bind to MHC Class I, transmitting a “don’t kill” signal that prevents the NK cell from attacking.
Cancer cells often attempt to hide from the immune system by reducing or entirely losing their surface expression of MHC Class I molecules, a strategy called “missing self”. When an NK cell encounters a cell with absent or reduced MHC Class I, the inhibitory signal is removed, tipping the balance toward activation. NK cells also express activating receptors that bind to stress-induced ligands, such as NKG2D ligands, which are frequently upregulated on the surface of tumor cells.
Once activated, the NK cell forms a tight connection, called an immunological synapse, with the target cell and initiates the killing process. The NK cell releases specialized compartments called lytic granules toward the cancer cell. These granules contain two primary destructive agents: perforin and granzymes. Perforin creates pores in the cancer cell membrane, allowing the granzymes to enter. Granzymes are enzymes that trigger programmed cell death, or apoptosis, in the cancer cell.
NK Cell Evasion: How Cancer Fights Back
Despite the effectiveness of NK cells, cancer can still progress because tumor cells develop sophisticated mechanisms to escape immune destruction. One common strategy involves the tumor microenvironment (TME), the complex network of cells and molecules surrounding the tumor. The TME can become immunosuppressive, neutralizing the NK cells that infiltrate the area.
Cancer cells and other cells within the TME often release immunosuppressive cytokines, most notably Transforming Growth Factor-beta (TGF-β). High levels of TGF-β can directly suppress NK cell function by reducing the expression of activating receptors, such as NKG2D. TGF-β also interferes with the NK cell’s ability to produce the cytotoxic molecules perforin and granzyme, blunting the killing mechanism.
Tumor cells can also upregulate inhibitory ligands that bind to certain receptors on the NK cell, effectively re-engaging a “don’t kill” signal despite activating signals. These evasive maneuvers can even cause NK cells to convert into a less cytolytic cell type, further diminishing the immune response.
Harnessing NK Cells for Immunotherapy
The ability of NK cells to rapidly target and kill cancer cells has made them valuable in the development of new cancer treatments. Scientists are enhancing the NK cell response through a method called adoptive cell transfer. This involves taking NK cells from a donor or the patient, expanding them in a laboratory, and then infusing these cells back into the patient.
A promising approach involves genetically modifying NK cells to express a Chimeric Antigen Receptor (CAR), resulting in CAR-NK cells. These CARs are engineered receptors that specifically recognize and bind to unique proteins found on the surface of cancer cells. This modification arms the NK cell with the precision of a targeted therapy while retaining its natural killing ability.
Unlike CAR T-cell therapy, CAR-NK cells can be derived from allogeneic sources, such as umbilical cord blood, making them an “off-the-shelf” product ready for immediate use. CAR-NK cells have also shown a lower risk of severe side effects, such as cytokine release syndrome, compared to their T-cell counterparts. Other strategies involve using drugs to block the immunosuppressive effects of molecules like TGF-β, which can restore the anti-tumor function of the patient’s existing NK cells.