Hypoxia downregulates the expression of activating receptors involved in NK‐cell‐mediated target cell killing without affecting ADCC

Abstract

In certain infection sites or tumor tissues, the disruption of homeostasis can give rise to a hypoxic microenvironment, which, in turn, can alter the function of different immune cell types and favor the progression of the disease. Natural killer (NK) cells are directly involved in the elimination of virus-infected or transformed cells, however it is unknownwhether their function is affected by hypoxia or not. In this study, we show that NK cells adapt to a hypoxic environment by upregulating the hypoxia-inducible factor 1α. However, NK cells lose their ability to upregulate the surface expression of the major activating NK-cell receptors (NKp46, NKp30, NKp44, and NKG2D) in response to IL-2 (or other activating cytokines, including IL-15, IL-12, and IL-21). These altered phenotypic features correlate with reduced responses to triggering signals resulting in impaired capability of killing infected or tumor target cells. Remarkably, hypoxia does not significantly alter the surface density and the triggering function of the Fc-γ receptor CD16, thus allowing NK cells to maintain their capability of killing target cells via antibody-dependent cellular cytotoxicity. This finding offers an important clue for exploitation of NK cell in antibody-based immunotherapy of cancer. Keywords: ADCC · Hypoxia · NK cells · Tumor Escape · Tumor MicroenvironmentAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAs a component of innate immunity, natural killer (NK) cells play an important role in the control of virus infections and in cancer immune surveillance [1][2][3][4][5]. They can kill a wide range of cells that, Correspondence: Prof. Lorenzo Moretta e-mail: lorenzomoretta@ospedale-gaslini.ge.it upon neoplastic transformation or virus infection, have downregulated major histocompatibility complex class I surface expression.To recognize their targets, NK cells use a complex array of activating receptors and/or coreceptors. These mainly include the natural cytotoxicity receptors (NCRs, i.e. NKp46, NKp30, and * These authors contributed equally to this work. * * These authors share senior authorship. [5,[11][12][13][14], there are still many obstacles for the effective use of these cells in immunotherapy. Both tumors and viruses have developed different escape mechanisms to avoid NK-cell immunosurveillance. For example, certain viruses can shape the expression profile of various NK-receptor ligands in infected cells [15]. Similarly, tumor cells may shed from the surface certain NKG2D ligands thus avoiding NK-cell-mediated attack [16]. In addition, several lines of evidence indicate that the tumor microenvironment may impact the real ability of NK cells to clear pathologic cells [17][18][19][20][21][22]. Indeed, while cytokines such as IL-2, IL-15, IL-12, and IL-21 can enhance NK-cell function, other factors induced at the tumor site, such as IDO, PGE 2 , and TGF-β, or even the direct interaction with tumor cells or tumor-associated stromal cells, may impai...

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“…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). Short term hypoxia (14 -17 h, 1% O 2 ) similarly reduced target cell killing, but sustaining hypoxia during the 4 -4.5-h cell killing assay contributed to this reduction (12,13).…”

Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

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