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Review
. 2020 Jun 16:10:874.
doi: 10.3389/fonc.2020.00874. eCollection 2020.

Immunomodulation of NK Cells by Ionizing Radiation

Jiarui Chen  1 , Xingyu Liu  1 , Zihang Zeng  1 , Jiali Li  1 , Yuan Luo  1 , Wenjie Sun  1 , Yan Gong  2   3 , Junhong Zhang  1   4   5 , Qiuji Wu  1   4   5 , Conghua Xie  1   4   5
Affiliations
Review

Immunomodulation of NK Cells by Ionizing Radiation

Jiarui Chen et al. Front Oncol. .

Abstract

Natural killer (NK) cells play a critical role in the antitumor immunity. Ionizing radiation (IR) has a pronounced effect on modifying NK cell biology, while the molecular mechanisms remain elusive. In this review, we briefly introduce the anti-tumor activity of NK cells and summarize the impact of IR on NK cells both directly and indirectly. On one hand, low-dose ionizing radiation (LDIR) activates NK functions while high-dose ionizing radiation (HDIR) is likely to partially impair NK functions, which can be reversed by interleukin (IL)-2 pretreatment. On the other hand, NK functions may be adjusted by other immune cells and the alternated malignant cell immunogenicity under the settings of IR. Various immune cells, such as the tumor-associated macrophage (TAM), dendritic cell (DC), regulatory T cell (Treg), myeloid-derived suppressor cell (MDSC), and tumor exhibited ligands, such as the natural killer group 2 member D ligand (NKG2DL), natural cytotoxicity receptors (NCR) ligand, TNF-related apoptosis-inducing ligand-receptor (TRAIL-R), and FAS, have been involved in this process. Better understanding the molecular basis is a promising way in which to augment NK-cell-based antitumor immunity in combination with IR.

Keywords: NK cell; immune response; immunotherapy; ionizing radiation; tumor.

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Figures

Figure 1
Figure 1
The impact of IR on NK cell. IR has a pronounced effect on modifying NK cell biology both directly and indirectly. On the one hand, IR induces the secretion of IFN-γ, TNF-α, perforin, and granzyme B of NK cells possibly through the p38-MAPK, ATM, and NF-κB pathway without alteration of activating receptors. On the other hand, IR programs the differentiation of classical activated macrophage (M1), which releases immunostimulatory IL-12 or IL-18 and triggers NK cytotoxicity. DC exposed to LDIR produces enhanced IL-2 and IFN-γ which promote NK functions while DC exposed to HDIR secretes less IL-12. IR also leads to the recruitment and activation of pro-tumor TAN phenotype (N2), alternatively activated macrophage (M2), Treg and MDSC which secrete TGF-β and impair NK activity. Finally, tumor expressed ligands, such as NKG2DL, TRAIL-R, and FAS, are upregulated during IR, enhancing the recognition of malignant cells by NK cells. However, PD-L1, classical HLA class I, sNKG2DL are also upregulated during IR, impairing the immunogenicity of tumor cells and NK cell recognition. See the main text for details. IR, ionizing radiation; NK cell, natural killer cell; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; MAPK, mitogen-activated protein kinase; ATM, ataxia telangiectasia mutated; NF-κB, nuclear factor kappa B; IL, interleukin; DC, dendritic cell; LDIR, low-dose ionizing radiation; HDIR, high-dose ionizing radiation; TAN, tumor-associated neutrophil; Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; TGF-β, transforming growth factor-β; NKG2DL, natural killer group 2 member D ligand; TRAIL-R, TNF-related apoptosis-inducing ligand-receptor; PD-L1, programmed death ligand 1; HLA, human leukocyte antigen; sNKG2DL, soluble natural killer group 2 member D ligand.
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