NKG2D ligands in tumor immunity

Abstract

The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, cd þ and CD8 þ T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed.

Natural killer cell immune escape in acute myeloid leukemia

“…Several cytokines have been described to affect the expression of NK cell activating receptors and activity of NK cells. 39,83,84 For example IFN-a, which has already been demonstrated to exert beneficial effects in AML patients 85,86 and to be a promoter of NK cell-mediated killing, upregulates the activating NKG2D receptor [87][88][89][90] and downregulates the inhibitory NKG2A receptors. 88 NKG2D and NCR expression in AML patients was also shown to be upregulated by IL-15, 26 a currently attractive therapeutic cytokine against AML 91 with strong NK-DC crosstalk potency.…”

“…51,93 Taken together, it will be interesting to assess the effect of immunotherapy with regard to enhancing NKG2D-mediated effector functions. 83 Direct escape from NK cell immunity in AML patients is also operated by an unfavorable NK cell inhibitory receptor phenotype (Table 1). Studies are ongoing to harness the reactivity of endogenous NK cells in patients with hematological malignancies, including AML, by administration of anti-KIR antibodies that can block NK cell inhibitory recognition without breaking selftolerance.…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…In humans, six ligands for NKG2D have been identified: MHC class I-related chains A and B (MICA and B) and four ULBP molecules (Bauer et al, 1999;Groh et al, 2001). NKG2D ligands are barely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cells or infected cells (Chitadze et al, 2013;Nausch and Cerwenka, 2008).…”

“…Thus, NKG2D receptor-ligand interactions play an important role in eliminating transformed or infected cells (Jonjić et al, 2008;Nausch and Cerwenka, 2008). Recent work has shown that various cellular stresses such as reactive oxygen species and DNA damage up-regulate MICA/B expression (Peraldi et al, 2009) and that dysregulated 5 expression of NKG2D ligands is involved in the development of inflammatory and autoimmune diseases such as rheumatoid arthritis, celiac disease and type 1 diabetes (Groh et al, 2003;Meresse et al, 2004;Ogasawara et al, 2004).…”

Shaping of NK Cell Responses by the Tumor Microenvironment

“…NKG2D, the best-characterized NK cell receptor in the context of tumor immunity, recognizes stress-induced ligands of the Rae1 protein family, H60 and MULT1 in mice, and MICA, MICB and members of ULBP family in humans. NKG2D ligands (NKG2D-Ls) are rarely expressed on healthy cells, but upregulated upon cellular transformation or viral infection [23,24]. Furthermore, chemotherapeutic drugs or ionizing radiation that cause activation of the DNA damage pathway can further upregulate NKG2D-L expression on tumor cells [25].…”