Abstract
Natural killer (NK) cells play a pivotal role in the immune system, especially in the recognition and clearance of cancer cells and infected cells. Their effector function is controlled by a delicate balance between the activating and inhibitory signals. We have identified 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) as NK cell receptors regulating NK cell cytotoxicity. Lectin-like transcript 1 (LLT1), a member of the C-type lectin-like domain family 2 (CLEC2D), induced IFN-γ production but did not directly regulate cytolytic activity. Interestingly, LLT1 expressed on other cells acts as a ligand for an NK cell inhibitory receptor NKRP1A (CD161) and inhibits NK cytolytic function. Extensive research has been done on novel therapies that target these receptors to increase the effector function of NK cells. The 2B4 receptor is involved in the rejection of melanoma cells in mice. Empliciti, an FDA-approved monoclonal antibody, explicitly targets the CS1 receptor and enhances the NK cell cytotoxicity against multiple myeloma cells. Our studies revealed that LLT1 is expressed on prostate cancer and triple-negative breast cancer cells and allows them to evade NK-cell-mediated killing. In this review, we describe NK cell receptors 2B4, CS1, and LLT1 and their potential in targeting cancer cells for NK-cell-mediated immunotherapy. New cancer immunotherapies like chimeric antigen receptor T (CAR-T) and NK (CAR-NK) cells are showing great promise in the treatment of cancer, and CAR cells specific to these receptors would be an attractive therapeutic option.
Highlights
Cancer remains a prevalent disease throughout the world and is a prolific area of active research.Cancer is categorized as metastatic and nonmetastatic, with metastatic cancer being the leading cause of death in cancer patients [1]
We have extensively studied the roles of 2B4, CS1, and lectin-like transcript 1 (LLT1) in targeting cancer cells for Natural killer (NK)-cell-mediated killing; the main focus of this review is on these three receptors
NK cells have a multitude of known receptors that interact with cancer cells
Summary
Cancer remains a prevalent disease throughout the world and is a prolific area of active research. Cancer is categorized as metastatic and nonmetastatic, with metastatic cancer being the leading cause of death in cancer patients [1]. Conventional therapies include the use of chemotherapy and radiation, but alternatives such as immunotherapy and the use of non-chemotherapeutic drugs are being researched. Conventional therapies are nonspecific as they kill cancer and healthy cells which could be very damaging to the individual as it can cause them to be in an immunosuppressive state whereby recurrent infections can occur [3,4]. The use of conventional therapies creates the possibility of further inducing mutations in cancer and noncancer cells [4,5,6]. The use of alternatives to chemotherapy and radiation offers benefit to individuals affected by cancer, as it decreases toxic side effects. It is more tolerable for the individual due to immune tolerance mechanisms established by the immune system [7]
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