Natural Killer Cells: Tumor Surveillance and Signaling

Abstract

Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.

Keywords: NK cells; Natural Killer cells; activating receptors; immune surveillance; inhibitory receptors; signaling.

Figure 1

Immunological synapse (IS) of Natural Killer (NK) cell and target cell. (A) NK cells engage other cells via integrins and adhesion molecules, which create the immunological synapse (IS)—the subsequent process between engagement and killing or tolerance can be broken down into four steps. (B) First, filamentous actin (F-actin) is recruited to the IS. Inside-out signaling reinforces IS interactions and activating and inhibitory surface receptors cluster at the IS. (C) Second, NK lytic granules move along microtubules by dynein-dynactin motor proteins toward the microtubule-organizing center (MTOC). (D) Third, the polarized lytic granules and MTOC travel in an ATP-dependent manner through the actin mesh via myosin IIA to dock at the IS, and finally, the lytic granules fuse with the membrane and release the lytic contents into the target cells, a process also known as degranulation. The NK cell then detaches and moves on to the next target.

Figure 2

NK cell surface receptors involved in tumor recognition. NK cells express a myriad of inhibitory and activating receptors designed to recognize healthy or aberrant (non-healthy) cells. (A) Inhibitory receptors dampen activating NK cell signals via cytoplasmic tyrosine motifs in their cytoplasmic tails, regulating NK cell effector function. (B) In contrast, most activating receptors signal through cytoplasmic adaptor proteins. Although many of the receptors are expressed by both mouse and human NK cells (shared), some are exclusive.

Figure 3

Inhibitory and activating NK cell signaling. NK cell effector function is collectively determined by the strongest activating or inhibitory signals. (A) Signaling downstream of inhibitory receptors is initiated by ligand engagement, followed by tyrosine phosphorylation of the signaling motif by Src-family kinases (SFK), Fyn or Lck. Once phosphorylated, there are three known inhibitory pathways: (1) Recruitment of SHP-1, SHP-2 or SHIP, which dephosphorylate Vav1; (2) Association with c-Abl kinase, which phosphorylates Crk disassociating it from its active complex and; (3) Phosphorylation and activation of Cbl-b by the TAM receptors. Cbl-b in turn ubiquitylates activating signaling intermediates such as LAT1 for degradation. (B) Signaling downstream of activating receptors is similarly transduced by tyrosine containing motifs that are phosphorylated by SFK. Various signaling intermediates such as Grb2, VAV1, or PI3K are then recruited, which induce cytotoxicity and cytokine release.