Cytokines Orchestrating the Natural Killer-Myeloid Cell Crosstalk in the Tumor Microenvironment: Implications for Natural Killer Cell-Based Cancer Immunotherapy

Abstract

Natural killer (NK) cells are endowed with germline-encoded receptors that enable them to detect and kill malignant cells without prior priming. Over the years, overwhelming evidence has identified an essential role for NK cells in tumor immune surveillance. More recently, clinical trials have also highlighted their potential in therapeutic settings. Yet, data show that NK cells can be dysregulated within the tumor microenvironment (TME), rendering them ineffective in eradicating the cancer cells. This has been attributed to immune suppressive factors, including the tumor cells per se, stromal cells, regulatory T cells, and soluble factors such as reactive oxygen species and cytokines. However, the TME also hosts myeloid cells such as dendritic cells, macrophages, neutrophils, and myeloid-derived suppressor cells that influence NK cell function. Although the NK-myeloid cell crosstalk can promote anti-tumor responses, myeloid cells in the TME often dysregulate NK cells via direct cell-to-cell interactions down-regulating key NK cell receptors, depletion of nutrients and growth factors required for NK cell growth, and secretion of metabolites, chemokines and cytokines that ultimately alter NK cell trafficking, survival, and cytotoxicity. Here, we review the complex functions of myeloid-derived cytokines in both supporting and suppressing NK cells in the TME and how NK cell-derived cytokines can influence myeloid subsets. We discuss challenges related to these interactions in unleashing the full potential of endogenous and adoptively infused NK cells. Finally, we present strategies aiming at improving NK cell-based cancer immunotherapies via pathways that are involved in the NK-myeloid cell crosstalk in the TME.

Keywords: cancer immunotherapy, tumor immunity; cytokines; myeloid cells; natural killer (NK) cells; tumor microenvironment.

Figure 1

Cytokines involved in the NK-myeloid cell cross talk in the tumor microenvironment. (A) A simplified schematic illustration showing the orchestra of myeloid- and NK cell-derived cytokines involved in forming anti-tumor immune responses by NK cells in the tumor microenvironment (TME). Activated NK cells produce IFN-γ which indirectly promotes recruitment of other NK cells from peripheral blood to the tumor sites. Upon recognition of tumor antigens, myeloid cells, especially DCs and macrophages produce inflammatory cytokines such as type-1 IFNs, IL-12, IL-15, IL-18, IL-21. These cytokines either alone or cooperatively promote NK cell survival, proliferation, maturation and production of spectrum of pro-inflammatory cytokines, including IFN-γ, TNF-α, GM-CSF, which further boost anti-tumor immune-activating potential of myeloid cells while recruiting additional inflammatory myeloid cells [including M1 macrophages (MQ), mature dendritic cells (DCs)] to sustain the anti-tumor immune response. Furthermore, myeloid-derived IL-23 and IL-27 cytokines can also promote NK cell activity by inducing IFN-γ production, but they can also negatively influence the NK-myeloid cell anti-tumor crosstalk by secretion of tumor-promoting cytokines such as IL-17 and IL-10, respectively. This suggests a dual role of IL-23 and IL-27 in NK cell-mediated tumor immunity. In line with the dual roles of certain cytokines, myeloid cells can become immune suppressive (myeloid-derived suppressor cells; MDSCs). This is frequently occurring during cancer progression. MDSCs secrete a plethora of immune suppressive cytokines that negatively influence the anti-tumor potential of NK cells per se but also impair anti-tumor responses normally resulting from the NK-myeloid cell crosstalk. For example, suppressive cytokines promote NK cell exhaustion and directly impair NK cell-mediated cytolytic activity, while limiting the ability of myeloid cells to produce NK cell stimulatory cytokines such as IL-12, IL-15, and IL-18. Green arrows indicate positive interactions and red arrows indicate negative interactions. (B) Therapeutic approaches that directly or indirectly modulate cytokine mediators that enhance NK cell-mediated anti-cancer responses in the TME. Simplified illustrations showing validated therapeutic approaches that can either restore or reinforce a stimulatory cytokine environment to augment NK cell-mediated tumor killing activity. On one hand, immunomodulatory drugs (IMiDs) such as lenalidomide can indirectly augment NK cell anti-tumor activity by reducing the levels of pro-tumorigenic factors, such as IL-6 and VEGF, while stimulating other immune cells to secrete IL-2. Accordingly, targeted blockade of immune-suppressive cytokines, such as IL-6, TGF-β can also positively impact NK-myeloid anti-tumor cross-talk in a similar manner. On the other hand, recombinant or synthetic cytokines as well as cell-based therapies such as cytokine-secreting CAR-NK cells can directly influence NK cell-mediated cancer cell killing. Importantly, cytokine-activated NK cells can further edit myeloid cells to enhance anti-tumor response via the production of inflammatory cytokines, such as IFN-γ. Light green arrows show the mode of therapeutic action.