Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity.

Anne-Sophie Chretien,Thomas Prebet,Didier Blaise,Daniel Olive,Aude Le Roy,Norbert Vey,Cyril Fauriat

doi:10.3389/fimmu.2014.00122

Abstract

Despite evidence of cancer immune-surveillance, which plays a key role in tumor rejection, cancer cells can escape immune recognition through different mechanisms. Thus, evasion to Natural killer (NK) cell-mediated anti-tumor activity is commonly described and is mediated by various mechanisms, mainly cancer cell-induced down-regulation of NK-activating receptors (NCRs, NKG2D, DNAM-1, and CD16) as well as up-regulation of inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs, NKG2A). Alterations of NK cells lead to an impaired recognition of tumor cells as well as a decreased ability to interact with immune cells. Alternatively, cancer cells downregulate expression of ligands for NK cell-activating receptors and up-regulate expression of the ligands for inhibitory receptors. A better knowledge of the extent and the mechanisms of these defects will allow developing pharmacological strategies to restore NK cell ability to recognize and lyse tumor cells. Combining conventional chemotherapy and immune modulation is a promising approach likely to improve clinical outcome in diverse neoplastic malignancies. Here, we overview experimental approaches as well as strategies already available in the clinics that restore NK cell functionality. Yet successful cancer therapies based on the manipulation of NK cell already have shown efficacy in the context of hematologic malignancies. Additionally, the ability of cytotoxic agents to increase susceptibility of tumors to NK cell lysis has been studied and may require improvement to maximize this effect. More recently, new strategies were developed to specifically restore NK cell phenotype or to stimulate NK cell functions. Overall, pharmacological immune modulation trends to be integrated in therapeutic strategies and should improve anti-tumor effects of conventional cancer therapy.

Highlights

Natural killer (NK) cells are key components of the innate immunity and substantially contribute to anti-tumor immune responses [1,2,3]
We focus on NK cells as a cornerstone to restore or improve anti-tumor immunity
Among the major mechanisms used by tumor cells to escape immunity, the evasion from receptor–ligand-mediated anti-tumor activity by NK cells represents the most prevalent pathway

Summary

Introduction

Natural killer (NK) cells are key components of the innate immunity and substantially contribute to anti-tumor immune responses [1,2,3]. In a phase II study, positive clinical outcomes were correlated with immune response to the vaccine and induction of immune enhancement of tumor antigen, but the effect on NK cells was not assessed [65]. This molecule is able to restore NKG2D expression on NK cells, whose expression was altered in vitro by cancer cell lines supernatants or direct inhibition with recombinant TGF-β [72].

Results

Conclusion