Introduction

Natural Killer (NK) cells are cytotoxic lymphocytes that innately recognize their target cells based on signals from an array of germline-encoded inhibitory and activating cell surface receptors (1). While inhibition is mainly mediated by HLA class I-binding receptors such as KIR, LIR-1, and NKG2A, activation is triggered by the NKG2D, DNAM-1, NKp30, NKp46, and 2B4 receptors, among others (2). Experimental approaches delineating how NK cells target tumor cells have in more recent years been harmonized with studies evidencing their role in tumor immune surveillance (3) and clinical therapy to treat patients with cancer (4, 5). However, it has also become increasingly clear that NK cells are often dysfunctional in cancer patients (6, 7). This is most prominent in the tumor microenvironment (TME), although also observed in blood and other tissues in patients with advanced cancer (6-8). Factors suppressing endogenous or adoptively infused NK cells in the TME are likely limiting the full potential of NK cell-based cancer immunotherapies.

NK cells can be disarmed in the TME by both direct and indirect interactions with the tumor cells (6, 7, 9). However, several other cell types in the TME, such as stroma cells and immune cells, acting by direct interactions and via release of reactive oxygen species, growth factors, and cytokines, can also induce NK cell dysfunction (9-11). Both the degree and mode of NK cell suppression in the TME may dynamically vary from early to later stages of cancer development as well as between different tumor histotypes. Beyond reducing the anti-tumor cytotoxicity of NK cells per se, suppression of NK cells in the TME can also negatively impact their ability to recruit other immune cells (12-15), which is crucial for initiating and maintaining proper anti-tumor responses. In this regard, a pivotal interaction in the TME is the one between NK cells and myeloid cells, such as dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs) (16-19). While NK cells positively promote DC infiltration and maturation via release of pro-inflammatory cytokines such as interferon (IFN)-γ (20), myeloid-derived cytokines, including interleukin (IL)-12, IL-15, and IL-18, critically promote NK cell maturation, proliferation, and anti-tumor functions (21). However, aggravation of the TME often observed in more advanced stages of cancer direct myeloid cells towards a suppressive phenotype that instead can impede NK cell functions via secretion of cytokines, such as transforming growth factor (TGF)-β, IL-1β, and IL-10 (22-24). Thus, the NK-myeloid crosstalk is intricate but critical for proper anti-tumor properties of NK cells in the TME.

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Here we give an overview of the cytokines involved in the interplay between NK cells and myeloid cells in the general TME. We discuss how myeloid cells promote NK cell functions and vice versa, but foremost, how this interaction can hinder NK cell-mediated tumor rejection. We outline current methods and possible future approaches to enhance anti-tumor responses by NK cells via administration or manipulation of cytokines and cytokine signaling, as well as preventing myeloid cell infiltration into the TME. This review highlights that a better understanding of the crosstalk between myeloid cells and NK cells is likely critical to improve the efficacy of NK cell-based cancer immunotherapy.

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