Killer immunoglobulin-like receptors and tumor immunity

Abstract

were originally named for their capacity to elicit potent cytotoxicity against tumor cells independent of prior sensitization or gene rearrangement. This process is facilitated through the expression of activating and inhibitory receptors that provide for NK cell "education" and a subsequent ability to survey, recognize, and lyse infected or transformed cells, especially those lacking or possessing mutated MHC class I expression. Since these original observations were made, how NK cells recognize candidate target cells continues to be the topic of ongoing investigation. It is now appreciated that NK cells express a diverse repertoire of activating and inhibitory receptors of which killer immunoglobulin-like receptors (KIR) appear to play a critical role in mediating self-tolerance as well as facilitating cytotoxicity against infected or transformed cells. In addition, in the presence of an activating signal, the absence or mismatch of MHC class I molecules on such targets (which serve as inhibitory KIR ligands) promotes NK cell–mediated lysis. An increasing understanding of the complexities of KIR biology has provided recent opportunities to leverage the NK cell versus tumor effect as a novel avenue of immunotherapy for cancer. The present review summarizes the current understanding of KIR expression and function and highlights ongoing efforts to translate these discoveries into novel NK cell–mediated immunotherapies for cancer.

Figure 1

Illustration of the concept of haploidentical allogeneic stem cell transplantation. NK cell cytotoxicity requires the presence of an activating signal and the absence or mismatch of MHC class I molecules on the target cell. (A). Autologous NK cell vs tumor cell, baseline with no lysis: On the left, a patient-derived, autologous NK cell with matched inhibitory KIR to the MHC class I self-molecule on the autologous tumor cell on the right; the NK cell receives an activating signal through the activating receptor-ligand interaction with a tumor cell; however, the NK cell is incapable of initiating a cytotoxic response due to the inhibitory signal resulting from an inhibitory KIR interaction with its cognate MHC class I self-molecule. (B) Mismatched inhibitory KIR/HLA→tumor cell lysis: On the left, a donor-derived NK cell with mismatched inhibitory KIR to the MHC class I ligand on the patient tumor cell on the right. The. mismatched NK cell lyses the target tumor cell in response to the activating signal because no inhibitory signal is delivered as a result of KIR/HLA ligand mismatch. (C). Anti-KIR blockade→tumor cell lysis: On the left, a patient-derived, autologous NK cell with matched inhibitory KIR to the MHC class I ligand on the autologous tumor cell. However, the presence of IPH2101, a monoclonal blocking antibody directed against the inhibitory KIR interrupts its binding to the cognate MHC class I ligand on the target cell resulting in a loss of the inhibitory signal thereby allowing for NK cell recognition and lysis of the tumor cell.