The Critical Role of the Tumor Microenvironment in Shaping Natural Killer Cell-Mediated Anti-Tumor Immunity

Abstract

Considerable evidence has been gathered over the last 10 years showing that the tumor microenvironment (TME) is not simply a passive recipient of immune cells, but an active participant in the establishment of immunosuppressive conditions. It is now well documented that hypoxia, within the TME, affects the functions of immune effectors including natural killer (NK) cells by multiple overlapping mechanisms. Indeed, each cell in the TME, irrespective of its transformation status, has the capacity to adapt to the hostile TME and produce immune modulatory signals or mediators affecting the function of immune cells either directly or through the stimulation of other cells present in the tumor site. This observation has led to intense research efforts focused mainly on tumor-derived factors. Notably, it has become increasingly clear that tumor cells secrete a number of environmental factors such as cytokines, growth factors, exosomes, and microRNAs impacting the immune cell response. Moreover, tumor cells in hostile microenvironments may activate their own intrinsic resistance mechanisms, such as autophagy, to escape the effective immune response. Such adaptive mechanisms may also include the ability of tumor cells to modify their metabolism and release several metabolites to impair the function of immune cells. In this review, we summarize the different mechanisms involved in the TME that affect the anti-tumor immune function of NK cells.

Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab

“…While the cellular stress response in transformed cells induces expression of membrane-bound MICA/ MICB, the cleavage of these molecules produces soluble forms of MICA and MICB capable of inhibiting interactions between membrane-bound MICA/MICB and NKG2D, thus desensitizing the activation signal through NKG2D in effector T cells and natural killer (NK) cells (33). The cleavage of membrane-bound MICA/MICB is promoted by the metalloprotease ADAM10 and is enhanced within hypoxic tumor environments (34). As hypoxia also promotes expression of immune inhibitory molecules (e.g., PD-L1 and LAG-3) and favors accumulation of regulatory immune cells (35), sMICA may be a biomarker that reflects this immunosuppressive tumor environment.…”

Short Term Hypoxia Synergizes with Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities

“…Our observation of target cell shifting to late apoptosis through hypoxic NK cell preculture leads us to speculate that oxygen availability during NK cell conditioning can modulate target cell death immunogenicity. This would not withstand hypoxia-mediated immunosuppression through tumor and stroma-derived factors (9,10). In fact, respiratory hyperoxia leads to NK cell-dependent regression of MCA205 pulmonary tumors in mice (72).…”

“…Therefore, they experience oxygen levels ranging from 5% in venous to 13% in arterial blood and down to 3-2% in healthy tissue and below (hypoxia) in the bone marrow, the lymphatic system, at sites of inflammation, and in the tumor microenvironment (3)(4)(5)(6)(7)(8)(9). Tumor hypoxia is thought to support tumor escape from NK cell-mediated cytotoxicity (9,10). In vitro, promotion of NK cell-mediated cell killing by interleukin-2 (IL-2) was reported to be reduced after 96 h at 1% O 2 compared with 20% O 2 , although antibody-dependent cellular cytotoxicity was not affected (11).…”

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

“…7 Extracellular vesicles represent a new component of this supportive microenvironment, are released by malignant cells and play an important role in cancer cell communication with their environment. [8][9][10][11] Exosomes are small vesicles (50-150 nm) generated via an endocytic pathway and are expressing chaperones (HSP70, HSP90) and tetraspanins (CD9, CD63, CD81). Exosomes contain proteins, DNA, noncoding RNAs, and mRNAs, and specific sorting mechanisms were proposed for loading selected molecules into exosomes.…”