Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.

Signaling for Synergistic Activation of Natural Killer Cells

Natural killer (NK) cells play a pivotal role in early surveillance against virus infection and cellular transformation, and are also implicated in the control of inflammatory response through their effector functions of direct lysis of target cells and cytokine secretion. NK cell activation toward target cell is determined by the net balance of signals transmitted from diverse activating and inhibitory receptors. A distinct feature of NK cell activation is that stimulation of resting NK cells with single activating receptor on its own cannot mount natural cytotoxicity. Instead, specific pairs of co-activation receptors are required to unleash NK cell activation via synergy-dependent mechanism. Because each co-activation receptor uses distinct signaling modules, NK cell synergy relies on the integration of such disparate signals. This explains why the study of the mechanism underlying NK cell synergy is important and necessary. Recent studies revealed that NK cell synergy depends on the integration of complementary signals converged at a critical checkpoint element but not on simple amplification of the individual signaling to overcome intrinsic activation threshold. This review focuses on the signaling events during NK cells activation and recent advances in the study of NK cell synergy.

Major Hepatectomy in the HCC Patient with an Indocyanine Green Retention Rate at 15 Minutes of 10% or Higher: Predictive Values of Postoperative Hepatic Failure

PURPOSE: Major hepatic resection is sometimes inevitable in patients with impaired liver function. We evaluated risk factors that cause postoperative liver failure after major hepatic resection in patients with over a 10% Indocyanine Green Retention rate at 15 minutes (ICGR15). METHODS: From Apr. 2002 to Aug. 2009, 32 patients who had over a 10% rate of ICGR15 underwent major hepatic resection (> or =4 Couinaud segments). Among the 32, 9 patients showed postoperative liver failure (less than 50% prothrombine time and/or 5 mg/dl or higher of total bilirubin). This high-risk group was compared to the rest who constituted a low-risk group. RESULTS: Patients with esophageal varix were more common in the high risk group (4 versus 2, p=0.043). Other clinicopathologic features showed no difference between the two groups. We had 2 in-hospital deaths in the high risk group. CONCLUSION: Great care is needed in patients with esophageal varix and limited liver function during major hepatic resection.